Tetrahydropyridothiophenes

ABSTRACT

Compounds of a certain formula (I) 
                         
in which Ra and Rb have the meanings indicated in the description, are novel effective compounds with anti-proliferative and apoptosis inducing activity.

This application was filed under 35 U.S.C. 371 as a national stage ofPCT/EP2006/062613, filed May 24, 2006.

FIELD OF APPLICATION OF THE INVENTION

The invention relates to tetrahydropyridothiophene derivatives, whichcan be used in the pharmaceutical industry for the production ofpharmaceutical compositions.

The invention further relates to the contribution made to the art by thefinding, that said tetrahydropyridothiophene derivatives displaycell-cycle dependent, anti-proliferative and apoptosis inducingactivity.

The invention also relates to the use of these compounds for the therapyof hyperproliferative diseases, in particular human cancer.

KNOWN TECHNICAL BACKGROUND

Cancer chemotherapy was established with the alkylating agentCyclophosphamide (Endoxan®), an oxazaphosphorin pro-drug activatedpreferentially in the tumor. The target of alkylating agents likeCyclophosphamide is DNA and the concept, that cancer cells withuncontrolled proliferation and a high mitotic index are killedpreferentially, proved to be very successful. Standard cancerchemotherapeutic drugs finally kill cancer cells upon induction ofprogrammed cell death (“apoptosis”) by targeting basic cellularprocesses and molecules. These basic cellular processes and moleculesinclude RNA/DNA (alkylating and carbamylating agents, platin analogs andtopoisomerase inhibitors), metabolism (drugs of this class are namedanti-metabolites and examples are folic acid, purin and pyrimidineantagonist) as well as the mitotic spindle apparatus with αβ-tubulinheterodimers as the essential component (drugs are categorized intostabilizing and destabilizing tubulin inhibitors; examples areTaxol/Paclitaxel®, Docetaxel/Taxotere® and vinca alkaloids).

A subgroup of proapoptotic anticancer agents target cells preferentiallyin mitosis. In general these agents do not induce apoptosis innon-dividing cells, arrested in the G0, G1 or G2 phase of the celldivision cycle. In contrast, dividing cells going through mitosis(M-phase of the cell division cycle), are killed efficiently byinduction of apoptosis by this subgroup agents. Therefore, this subgroupor class of anti-cancer agents is described as cell-cycle specific orcell-cycle dependent. Tubulin inhibitors, with Taxol (Paclitaxel®) as aprominent example, belong to this class of cell-cycle specific,apoptosis inducing anti-cancer agents.

The international application WO2004/024065 describes, inter alia,tetrahydropyridothiophene derivatives as glucagons antagonists for thetreatment of diabetes.

The german document DE4039734 describes, inter alia, N-alkylatedtetrahydropyridothiophene derivatives as components of herbicidalagents.

The german document DD272078 describes, inter alia, N-alkylatedtetrahydropyridothiophene derivatives with antianaphylactic undantihistaminergic properties.

The international application WO2005/033102 describes thiophene-basedcompounds exhibiting ATP-utilizing enzyme inhibitory activity.

The international application WO2004/092156 describes substituted3-cyanothiophene acetamides as glucagon receptor antagonists.

The international application WO9946267 describes 2-aminothiophenederivatives as modulators of protein tyrosine phosphatases.

The international application WO2005/060711 describes a method oftreating diseases mediated by sirtuin, e.g. SirT1 mediateddeacetylation, using substituted thiophene compounds.

The international application WO2005/033102 describes a method ofcombating phytopathogenic diseases on plants using 2-aminothiophenederivatives.

The international application WO2004/069149 describesaminosulfonyl-substituted thienopyridine derivatives which are said tobe capable of inhibiting the interactions between effector cell adhesionmolecules and glycosaminoglycans and thus useful for treating diseasesrelated to cell adhesion and cell migration.

The international applications WO2005/118071, WO2005/118592 andWO2005/120642 describe tetrahydropyridothiophenes withanti-proliferative and/or apoptosis inducing activity for use in thetreatment of cancer.

DESCRIPTION OF THE INVENTION

It has now been found that the tetrahydropyridothiophene derivatives,which are described in greater details below, differ from prior artcompounds by unanticipated and originative structural alterations andhave surprising and particularly advantageous properties.

Thus, for example, the compounds according to this invention are potentand highly efficacious inhibitors of cellular (hyper)proliferationand/or cell-cycle specific inducers of apoptosis in cancer cells.

Therefore, unanticipatedly, these compounds can be useful for treating(hyper)proliferative diseases and/or disorders responsive to theinduction of apoptosis, in particular cancer. By having a cell-cyclespecific mode of action, these derivates should have a highertherapeutic index compared to standard chemotherapeutic drugs targetingbasic cellular processes like DNA replication or interfering with basiccellular molecules like DNA.

Thus, for example, the compounds according to this invention areexpected to be useful in targeted cancer therapy.

The invention thus relates, in a first aspect (aspect a), to compoundsof formula I

wherein

-   Ra is —C(O)R1, in which-   R1 is 1-4C-alkyl, or 1-4C-alkyl substituted by one to four    substituents independently selected from R2,-   Rb is -T-Q, in which-   T is 1-6C-alkylene or 3-7C-cycloalkylene, and-   either-   Q is optionally substituted by Rba and/or Rbb and/or Rbc, and is    phenyl or naphthyl,-   or-   Q is optionally substituted by Rca and/or Rcb, and is Har,-   or-   Q is optionally substituted by Rda and/or Rdb, and is Het,-   or-   Q is optionally substituted by Rea and/or Reb, and is    3-7C-cycloalkyl,    wherein-   each R2 may be the same or different and is independently selected    from the group consisting of:    -   3-7C-cycloalkyl, phenyl, Har, Het,    -   halogen, trifluoromethyl, nitro, cyano,    -   —C(O)R3, —C(O)OR4, —C(O)N(R5)R6, —S(O)₂R3, —S(O)₂N(R5)R6,    -   —N(R7)C(O)R3, —N(R7)C(O)OR4, —N(R7)C(O)N(R5)R6, guanidino,    -   —OC(O)R3,    -   completely or predominantly fluorine-substituted 1-4C-alkoxy,    -   —O[C(R8)R9]_(y)N(R5)R6, —O[C(R8)R9]_(y)C(O)N(R5)R6,    -   —OR4, hydroxy-2-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,        pyridyl-1-4C-alkoxy, (1-4C-alkoxy-2-4C-alkoxy-2-4C-alkoxy,        —N(R5)R6, and —SR3,    -   wherein each of said 3-7C-cycloalkyl, phenyl, Har and Het is        optionally substituted by one to four substituents independently        selected from R10,    -   in which-   each R3, R4, R5 and R6 may be the same or different and is each    independently selected from the group consisting of:    -   hydrogen, 1-7C-alkyl, 3-7C-cycloalkyl, phenyl, and        phenyl-1-4C-alkyl,-   each R7 may be the same or different and is independently selected    from the group consisting of:    -   hydrogen, 1-7C-alkyl, and 3-7C-cycloalkyl,-   each R8 and R9 may be the same or different and is each    independently selected from the group consisting of:    -   hydrogen, and 1-4C-alkyl,-   each R10 may be the same or different is independently selected from    the group consisting of:    -   1-4C-alkyl, phenyl,    -   halogen, trifluoromethyl, cyano,    -   1-4C-alkoxycarbonyl, carboxyl,    -   hydroxyl, and phenoxy,    -   wherein each of said phenyl and phenoxy radicals can be        unsubstituted or optionally substituted by up to four halogen        radicals and up to two 1-4C-alkyl, hydroxyl, trifluoromethyl or        cyano radicals,-   each y is 1, 2, 3 or 4,-   each Rba, Rbb, Rbc, Rca, Rcb, Rda, Rdb, Rea and Reb may be the same    or different and is each independently selected from the group    consisting of:    -   1-4C-alkyl, phenyl,    -   halogen, trifluoromethyl, cyano,    -   1-4C-alkoxycarbonyl, carboxyl,    -   hydroxyl, and phenoxy,    -   wherein each of said phenyl and phenoxy can be unsubstituted or        optionally substituted by up to four halogen radicals and up to        two 1-4C-alkyl, hydroxyl, trifluoromethyl or cyano radicals,-   each Har is the same or different and is independently any fully    aromatic or partially aromatic mono- or fused bicyclic ring or ring    system made up of-   a first constituent being a 5- or 6-membered monocyclic unsaturated,    aromatic heteroaryl ring A,    -   which heteroaryl ring A comprises one to four heteroatoms        independently selected from nitrogen, oxygen and sulfur,-   and, optionally, fused to said first constituent,-   a second constituent being a benzene ring, a 5-6C-cycloalkane ring,    an additional heteroaryl ring A as defined herein afore, or a    heterocyclic ring B as defined herein below,    whereby said Har ring or ring system is attached to the parent    molecular group via a substitutable ring carbon or ring nitrogen    atom,-   each Het is the same or different and is independently any fully    saturated or partially unsaturated mono- or fused bicyclic ring or    ring system made up of-   a first constituent being a 3- to 7-membered monocyclic fully    saturated or partially unsaturated, non-aromatic heterocyclic ring    B,    -   which heterocyclic ring B comprises one to three heteroatoms        independently selected from nitrogen, oxygen and sulfur,    -   and which heterocyclic ring B is optionally substituted by one        or two oxo groups,-   and, optionally, fused to said first constituent,-   a second constituent being a benzene ring, a 3-7C-cycloalkane ring,    or an additional heterocyclic ring B as defined herein afore,    whereby said Het ring or ring system is attached to the parent    molecular group via a substitutable ring carbon or ring nitrogen    atom;-   under the proviso, that-   (6-acetyl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide-   is thereof disclaimed;-   and the salts thereof.

1-4C-Alkyl is a straight-chain or branched alkyl radical having 1 to 4carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl,propyl, isopropyl, and, particularly, the ethyl and methyl radicals.

1-6C-Alkylene is a straight chain or branched alkylene radical having 1to 4 carbon atoms. Examples which may be mentioned in this context arethe methylene (—CH₂—), ethylene (—CH₂—CH₂—), trimethylene(—CH₂—CH₂—CH₂—), tetramethylene (—CH₂—CH₂—CH₂—CH₂—),1,2-dimethylethylene [—CH(CH₃)—CH(CH₃)—], 1,1-dimethylethylene[—C(CH₃)₂—CH₂—], 2,2-dimethylethylene [—CH₂—C(CH₃)₂—], isopropylidene[—C(CH₃)₂—], 1-methylethylene radical [—CH(CH₃)—CH₂—], 2-methylethyleneradical [—CH₂—CH(CH₃)—], pentamethylene (—CH₂—CH₂—CH₂—CH₂—CH₂—) and thehexamethylene radicals (—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—), of which the1-4C-alkylene radicals, in particular the ethylene, the2,2-dimethylethylene, the 1-methylethylene and the 2-methylethyleneradicals, are more worthy to be mentioned. In more particular worthy tobe mentioned are the ethylene and the 2-methylethylene [—CH₂—CH(CH₃)—]radicals. It is to be understood, that, when T is one of those1-6C-alkylene radicals drawn above, said radical is attached with itsright terminus to the moiety Q.

3-7C-Cycloalkyl stands for cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl, of which cyclopropyl, cyclopentyl andcyclohexyl are to be emphasized.

3-7C-Cycloalkane stands for cyclopropane, cyclobutane, cyclopentane,cyclohexane and cycloheptane, of which cyclohexane and cyclopentane areto be emphasized.

5-6C-Cycloalkane stands for cyclohexane and cyclopentane.

3-7C-Cycloalkylene represents cycloalkylene radicals having 3 to 7carbon atoms, such as cyclopropylene, cyclobutylene, cyclopentylene,cyclohexylene and cycloheptylene, of which cyclopropylene is more worthyto be mentioned, where the 1,2-cyclopropylene radical is to beemphasized.

Phenyl-1-4C-alkyl represents one of the abovementioned 1-4C-alkylradicals, which is substituted by a phenyl radical. Examples which maybe mentioned are the phenethyl and the benzyl radicals.

Halogen within the meaning of the present invention is iodine, or,particularly, bromine, chlorine and fluorine.

1-4C-Alkoxy represents radicals which, in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 1 to 4 carbonatoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxyand methoxy radicals.

2-4C-Alkoxy represents radicals which, in addition to the oxygen atom,contain a straight-chain or branched alkyl radical having 2 to 4 carbonatoms. Examples which may be mentioned are the butoxy, isobutoxy,sec-butoxy, tert-butoxy, propoxy, isopropoxy and preferably the ethoxyradical.

As completely or predominantly fluorine-substituted 1-4C-alkoxy, forexample, the 2,2,3,3,3-penta-fluoropropoxy, the perfluoroethoxy, the1,2,2-trifluoroethoxy, in particular the 1,1,2,2-tetrafluoroethoxy, the2,2,2-trifluoroethoxy, the trifluoromethoxy and preferably thedifluoromethoxy radicals may be mentioned. “Predominantly” in thisconnection means that more than half of the hydrogen atoms of the1-4C-alkoxy radicals are replaced by fluorine atoms.

1-4C-Alkoxy-2-4C-alkoxy represents 2-4C-alkoxy radicals, which aresubstituted by one of the abovementioned 1-4C-alkoxy radicals. Exampleswhich may be mentioned are the methoxyethoxy, ethoxyethoxy and theisopropoxyethoxy radicals, particularly the 2-methoxyethoxy,2-ethoxyethoxy and the 2-isopropoxyethoxy radicals.

Phenyl-1-4C-alkoxy represents one of the abovementioned 1-4C-alkoxyradicals, which is substituted by a phenyl radical. Examples which maybe mentioned are the phenethoxy and the benzyloxy radicals.

Pyridyl-1-4C-alkoxy represents one of the abovementioned 1-4C-alkoxyradicals, which is substituted by a pyridyl radical. Examples which maybe mentioned are the 2-pyridyl-ethoxy and the pyridylmethoxy radicals.

Pyridyl-1-4C-alkyl represents one of the abovementioned 1-4C-alkylradicals, which is substituted by a pyridyl radical. Examples which maybe mentioned are the 2-pyridyl-ethyl and the pyridylmethyl radicals.

Pyridyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.

(1-4C-Alkoxy-2-4C-alkoxy)-2-4C-alkoxy represents 2-4C-alkoxy radicals,which are substituted by one of the abovementioned1-4C-alkoxy-2-4C-alkoxy radicals. Examples which may be mentioned arethe 2-(2-methoxyethoxy)-ethoxy and the 2-(2-ethoxyethoxy)-ethoxyradicals.

Hydroxy-2-4C-alkoxy represents 2-4C-alkoxy radicals, which aresubstituted by a hydroxyl group. Examples which may be mentioned are the2-hydroxyethoxy and the 3-hydroxypropoxy radicals. 1-4C-Alkoxycarbonylrepresents a radical which, in addition to the carbonyl group, containsone of the abovementioned 1-4C-alkoxy radicals. Examples which may bementioned are the methoxycarbonyl, the ethoxycarbonyl and thetertbutoxycarbonyl radicals.

In addition to the nitrogen atom, mono- or di-1-4C-alkylamino radicalscontain one or two of the abovementioned 1-4C-alkyl radicals.Di-1-4C-alkylamino is preferred and here, in particular, dimethyl-,diethyl- or diisopropylamino.

Mono- or Di-1-4C-alkylaminocarbonyl radicals contain in addition to thecarbonyl group one of the abovementioned mono- or di-1-4C-alkylaminoradicals. Examples which may be mentioned are the N-methyl- theN,N-dimethyl-, the N-ethyl-, the N-propyl-, the N,N-diethyl- and theN-isopropylaminocarbonyl radical.

An 1-4C-Alkylcarbonylamino radical is, for example, the propionylamino(C₃H₇C(O)NH—) and the acetylamino radical (CH₃C(O)NH—).

1-4C-Alkylcarbonyloxy stands for a carbonyloxy group to which one of theabovementioned 1-4C-alkyl radicals is bonded. An example is the acetoxyradical (CH₃C(O)—O—).

1-4C-Alkylcarbonyl is a carbonyl group to which one of theabovementioned 1-4C-alkyl radicals is bonded. An example is the acetylradical (CH₃CO—).

Naphthyl includes naphthalen-1-yl and naphthalen-2-yl.

Har stands for a fully aromatic or partially aromatic mono- or fusedbicyclic ring or ring system made up of

-   a first constituent being a 5- or 6-membered monocyclic unsaturated,    aromatic heteroaryl ring A, which heteroaryl ring A comprises one to    four heteroatoms independently selected from nitrogen, oxygen and    sulfur,-   and, optionally, fused to said first constituent,-   a second constituent being a benzene ring, a 5-6C-cycloalkane ring,    an additional heteroaryl ring A as defined herein afore, or a    heterocyclic ring B as defined herein below in the context of the    definition of Het,    whereby said Har ring or ring system is attached to the parent    molecular group via a substitutable ring carbon or ring nitrogen    atom.

It is to be understood, that, if a radical Har contains quaternizableimino-type ring nitrogen atoms (—N═), said Har radical is not attachedvia said quaternizable imino-type ring nitrogen atom to the parentmolecular group.

Examples for Har may include, but are not limited to, 5-memberedheteroaryl radicals, such as e.g. furanyl, thiophenyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,triazolyl, thiadiazolyl or oxadiazolyl, and 6-membered heteroarylradicals, such as e.g. pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,

and the benzo-fused derivatives thereof such as e.g. quinazolinyl,quinoxalinyl, cinnolinyl, quinolinyl, isoquinolinyl, indolyl,isoindolyl, indazolyl, phthalazinyl, benzothiophenyl, benzofuranyl,isobenzofuranyl, benzoxazolyl, benzothiazolyl or benzimidazolyl, as wellas naphthyridinyl, indolizinyl or purinyl.

When R2 is Har, a more detailed example for Har includes imidazolyl.

When R2 is Har, a further more detailed example for Har includesimidazol-1-yl.

When R2 is Har, a further more detailed example for Har includesimidazol-4-yl and, particularly, imidazol-5-yl and imidazol-2-yl.

When R2 is Har, another more detailed example for Har includespyridinyl.

When R2 is Har, a further more detailed example for Har includespyridin-2-yl.

When R2 is Har, another further more detailed example for Har includespyridin-3-yl.

When R2 is Har, another further more detailed example for Har includespyridin-4-yl.

When Q is Har, a more detailed example for Har includes pyridinyl.

When Q is Har, a further more detailed example for Har includespyridin-2-yl.

When Q is Har, another further more detailed example for Har includespyridin-3-yl.

When Q is Har, another more detailed example for Har includes furanyl.

When Q is Har, a further more detailed example for Har includesfuran-2-yl.

When Q is Har, another further more detailed example for Har includesfuran-3-yl.

When Q is Har, another more detailed example for Har includesthiophenyl.

When Q is Har, a further more detailed example for Har includesthiophen-2-yl.

When Q is Har, another further more detailed example for Har includesthiophen-3-yl.

Het stands for a fully saturated or partially unsaturated mono- or fusedbicyclic ring or ring system made up of

-   a first constituent being a 3- to 7-membered monocyclic fully    saturated or partially unsaturated, non-aromatic heterocyclic ring    B,    -   which heterocyclic ring B comprises one to three heteroatoms        independently selected from nitrogen, oxygen and sulfur,    -   and which heterocyclic ring B is optionally substituted by one        or two oxo groups,-   and, optionally, fused to said first constituent,-   a second constituent being a benzene ring, a 3-7C-cycloalkane group,    or an additional heterocyclic ring B as defined herein afore,    whereby said Het ring or ring system is attached to the parent    molecular group via a substitutable ring carbon or ring nitrogen    atom.

Examples for Het may include, but are not limited to, aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, pyrazolidinyl,imidazolidinyl, piperazinyl, homopiperazinyl, morpholinyl orthiomorpholinyl, or tetrahydrofuranyl,

and the partially unsaturated derivatives thereof such as e.g.pyrrolinyl, imidazolinyl or pyrazolinyl, and the oxo substitutedderivatives of the aforementioned examples such as e.g.2-oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl, 2,6-dioxopiperidinyl,2-oxopiperazinyl, or 5-oxo-1,4-diazepanyl,and the benzo-fused derivatives of the aforementioned examples such ase.g. indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolinyl or1,2,3,4-tetrahydroisoquinolinyl,as well as 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl,2,3-dihydrobenzothiophenyl, chromenyl, chromanyl, or2,3-dihydrobenzofuranyl.

More detailed exemplary Het radicals include those isomers of theabovementioned examples which are attached via a ring nitrogen atom,such as e.g., without being limited to,

aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl,homopiperidin-1-yl, piperazin-1-yl, homopiperazin-1-yl, morpholin-4-ylor thiomorpholin-4-yl.

Other more detailed exemplary Het radicals include those isomers of theabovementioned examples which are attached via a ring carbon atom, suchas e.g., without being limited to,

pyrrolidin-2-yl, pyrrolidin-2-yl, piperidin-2-yl, piperidin-3-yl,piperidin-4-yl or piperazin-2-yl.

Other more detailed exemplary Het radicals include those benzo-fusedderivatives which are attached via the benzene ring to the parentmolecular group, such as e.g. 1,3-benzodioxol-5-yl,2,3-dihydro-1,4-benzodioxin-6-yl, 2,3-dihydrobenzothiophen-5-yl,2,3-dihydrobenzothiophen-6-yl, chromen-6-yl, chromen-7-yl, chroman-6-yl,chroman-7-yl, 2,3-dihydrobenzofuran-5-yl, or2,3-dihydrobenzofuranyl-6-yl.

When R2 is Het, further more detailed exemplary Het radicals includemorpholino (i.e. morpholin-4-yl).

As used herein, the term “oxo” forms a carbonyl moiety when attached ata carbon atom, a sulfoxide moiety when attached to a sulfur atom and asulfonyl moiety when two of said terms are attached to a sulfur atom.

Mono- or di-(R201)-substituted imidazol-1-yl or pyrazol-1-yl stands foran imidazol-1-yl or pyrazol-1-yl radical, respectively, which issubstituted by one or two radicals independently selected from R201,such as mono- or di-methyl-substituted imidazol-1-yl or pyrazol-1-yl,respectively, like 2-methyl-imidazol-1-yl, 4-methyl-imidazol-1-yl or5-methyl-imidazol-1-yl, or 2,4-dimethyl-imidazol-1-yl; in particular2-methyl-imidazol-1-yl, 4-methyl-imidazol-1-yl or2,4-dimethyl-imidazol-1-yl.

R201- and/or R202-substituted pyridyl or pyrimidinyl, respectively, mayinclude, for example, methyl-substituted pyridyl or pyrimidinyl,respectively, like 4-methyl-pyridin-2-yl or 4-methyl-pyridin-3-yl.

1N-(1-4C-alkyl)-imidazolyl or 1N-(1-4C-alkyl)-pyrazolyl, respectively,refers to imidazolyl or pyrazolyl, respectively, which is substituted by1-4C-alkyl on the nitrogen atom in position 1, such as e.g.1N-methyl-imidazolyl or 1N-ethyl-imidazolyl, e.g.1-methyl-imidazol-2-yl, 1-methyl-imidazol-5-yl or 1-ethyl-imidazol-2-yl;in particular 1-methyl-imidazol-2-yl or 1-methyl-imidazol-5-yl.R201-substituted 1N-(1-4C-alkyl)-imidazolyl or R201-substituted1N-(1-4C-alkyl)-pyrazolyl, respectively, may include, for example,methyl- or ethyl-substituted 1N-(1-4C-alkyl)-imidazolyl or1N-(1-4C-alkyl)-pyrazolyl, respectively, like methyl-substituted1N-methyl-imidazolyl, e.g. 1,4-dimethyl-imidazol-2-yl or1,5-dimethylimidazol-2-yl.

1N—(H)-imidazolyl or 1N—(H)-pyrazolyl, respectively, refers toimidazolyl or pyrazolyl, respectively, which is substituted by hydrogenon the nitrogen atom in position 1, such as e.g. 1H-imidazol-2-yl or1H-imidazol-5-yl. R201-substituted 1N—(H)-imidazolyl or R101-substituted1N—(H)-pyrazolyl, respectively, may include, for example, methyl- orethyl-substituted 1N—(H)-imidazolyl or 1N—(H)-pyrazolyl, respectively,like methyl-substituted 1N—(H)-imidazolyl, e.g.4-methyl-1H-imidazol-2-yl or 5-methyl-1H-imidazol-2-yl.

The term (R2)-methyl stand for methyl which is substituted by R2. Theterm 2-(R2)-ethyl stands for ethyl which is substituted in 2-position byR2. The term 3-(R2)-propyl stands for propyl which is substituted in3-position by R2.

The expression (Rba)-phenyl means that the phenyl radical is substitutedby Rba, which is attached to any of the positions of the phenyl ring;the expression 2-(Rba)-phenyl means that the phenyl radical issubstituted by Rba, which is attached in the 2-position to the phenylradical (i.e. the ortho position with respect to the binding position inwhich the phenyl ring is bonded to the parent molecular group). Theexpression 5-(Rca)-furan-2-yl means that the furan-2-yl radical issubstituted by Rca, which is attached in the 5-position to thefuran-2-yl radical; the expression 5-(Rca)-4-(Rcb)-furan-2-yl means thatthe furan-2-yl radical is substituted by both Rca and Rcb, whereby thesubstituent Rca is bonded in the 5-position to the furan-2-yl radical,and the substituent Rcb is bonded in the 4-position to the furan-2-ylradical. In this connection, further similar expressions mentionedherein indicating in short form the positions in which substituents arebonded to a ring radical are to be understood similarly, mutatismutandis, as specified exemplarily and representatively for theforegoing expressions.

In general, unless otherwise mentioned, the radicals Har and Het includeall the possible isomeric forms thereof, particularly the positionalisomers thereof. Thus, for example, the term pyridinyl or pyridylincludes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, or the termthiophenyl includes thiophen-2-yl and thiophen-3-yl.

Constituents which are optionally substituted as stated herein, may besubstituted, unless otherwise noted, at any possible position.

Unless otherwise mentioned, the phenyl radical may be substituted by itssubstituents or parent molecular groups at any possible position.

The heterocyclic groups, alone or as part of other groups, mentionedherein may be substituted by their given substituents or parentmolecular groups, unless otherwise noted, at any possible position, suchas e.g. at any substitutable ring carbon or ring nitrogen atom.

Unless otherwise noted, rings containing quaternizable imino-type ringnitrogen atoms (—N═) may be preferably not quaternized on theseimino-type ring nitrogen atoms by the mentioned substituents or parentmolecular groups.

Unless otherwise noted, any heteroatom of a heterocyclic ring withunsatisfied valences mentioned herein is assumed to have the hydrogenatom(s) to satisfy the valences.

When any variable occurs more than one time in any constituent, eachdefinition is independent.

Suitable salts for compounds of formula I according to thisinvention—depending on substitution—are all acid addition salts or allsalts with bases. Particular mention may be made of thepharmacologically tolerable inorganic and organic acids and basescustomarily used in pharmacy. Those suitable are, on the one hand,water-insoluble and, particularly, water-soluble acid addition saltswith acids such as, for example, hydrochloric acid, hydrobromic acid,phosphoric acid, nitric acid, sulphuric acid, acetic acid, citric acid,D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl)benzoic acid, butyricacid, sulphosalicylic acid, maleic acid, lauric acid, malic acid,fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid,stearic acid, toluenesulphonic acid, methanesulphonic acid or3-hydroxy-2-naphthoic acid, the acids being employed in saltpreparation—depending on whether a mono- or polybasic acid is concernedand depending on which salt is desired—in an equimolar quantitativeratio or one differing therefrom.

On the other hand, salts with bases are—depending on substitution—alsosuitable. As examples of salts with bases are mentioned the lithium,sodium, potassium, calcium, aluminium, magnesium, titanium, ammonium,meglumine or guanidinium salts, here, too, the bases being employed insalt preparation in an equimolar quantitative ratio or one differingtherefrom.

Pharmacologically intolerable salts, which can be obtained, for example,as process products during the preparation of the compounds according tothis invention on an industrial scale, are converted intopharmacologically tolerable salts by processes known to the personskilled in the art.

According to expert's knowledge the compounds of formula I according tothis invention as well as their salts may contain, e.g. when isolated incrystalline form, varying amounts of solvents. Included within the scopeof the invention are therefore all solvates and in particular allhydrates of the compounds of formula I according to this invention aswell as all solvates and in particular all hydrates of the salts of thecompounds of formula I according to this invention.

In one embodiment of this invention, salts of compounds of formula Iinclude a salt of a compound of formula I selected from the groupconsisting of a hydrochloride salt, a malonate salt, a tartrate salt,(such as e.g. a D-(−)-tartrate salt or a L-(+)-tartrate salt), a maleatesalt, a methanesulfonate salt and an oxalate salt.

In the context of this invention, hyperproliferation and analogous termsare used to describe aberrant/dysregulated cellular growth, a hallmarkof diseases like cancer. This hyperproliferation might be caused bysingle or multiple cellular/molecular alterations in respective cellsand can be, in context of a whole organism, of benign or malignantbehaviour. Inhibition of cell proliferation and analogous terms is usedherein to denote an ability of the compound to retard the growth ofand/or kill a cell contacted with that compound as compared to cells notcontacted with that compound. Most preferable this inhibition of cellproliferation is 100%, meaning that proliferation of all cells isstopped and/or cells undergo programmed cell death. In some preferredembodiments the contacted cell is a neoplastic cell. A neoplastic cellis defined as a cell with aberrant cell proliferation and/or thepotential to metastasize to different tissue or organs. A benignneoplasia is described by hyperproliferation of cells, incapable offorming an aggressive, metastasizing tumor in-vivo. In contrast, amalignant neoplasia is described by cells with different cellular andbiochemical abnormalities, e.g. capable of forming tumor metastasis. Theacquired functional abnormalities of malignant neoplastic cells (alsodefined as “hallmarks of cancer”) are replicative potential(“hyperproliferation”), self-sufficiency in growth signals,insensitivity to anti-growth signals, evasion from apoptosis, sustainedangiogenesis and tissue invasion and metastasis.

Inducer of apoptosis and analogous terms are used herein to identify acompound which executes programmed cell death in cells contacted withthat compound. Apoptosis is defined by complex biochemical events withinthe contacted cell, such as the activation of cystein specificproteinases (“caspases”) and the fragmentation of chromatin. Inductionof apoptosis in cells contacted with the compound might not necessarilybe coupled with inhibition of cell proliferation. Preferably, theinhibition of cell proliferation and/or induction of apoptosis isspecific to cells with aberrant cell growth (hyperproliferation). Thus,compared to cells with aberrant cell growth, normal proliferating orarrested cells are less sensitive or even insensitive to theproliferation inhibiting or apoptosis inducing activity of the compound.Finally, cytotoxic is used in a more general sense to identify compoundswhich kill cells by various mechanisms, including the induction ofapoptosis/programmed cell death in a cell cycle dependent or cell-cycleindependent manner.

Cell cycle specific and analogous terms are used herein to identify acompound as inducing apoptosis only in continously proliferating cellsactively passing a specific phase of the cell cycle, but not in resting,non-dividing cells. Continously proliferating cells are typical fordiseases like cancer and characterized by cells in all phases of thecell division cycle, namely in the G (“gap”) 1, S (“DNA synthesis”), G2and M (“mitosis”) phase.

Compounds according to aspect a of the present invention more worthy tobe mentioned include those compounds of formula I as defined at theoutset, or, particularly, of formulae Ia, Ib, Ic, Id or Id′ as shownbelow

wherein

-   Ra is —C(O)R1, in which-   R1 is 1-4C-alkyl, or 1-C-alkyl substituted by one or two    substituents independently selected from R2,-   Rb is -T-Q, in which-   T is 1-6C-alkylene or 3-7C-cycloalkylene, and-   either-   Q is optionally substituted by Rba and/or Rbb and/or Rbc, and is    phenyl,-   or-   Q is optionally substituted by Rca and/or Rcb, and is Har,-   or-   Q is attached via a carbon atom of the benzene ring to the parent    molecular group, and is 1,3-benzodioxolyl,    2,2-difluoro-1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl,    2,3-dihydrobenzofuranyl, chromenyl or chromanyl,-   or-   Q is attached via a carbon atom of the benzene ring to the parent    molecular group, and is benzofuranyl,-   or-   Q is tetrahyrofuranyl,-   or-   Q is 3-7C-cycloalkyl,    wherein-   each R2 may be the same or different and is independently selected    from the group consisting of:    -   Har, Het,    -   —C(O)R3, —C(O)OR4, —C(O)N(R5)R6,    -   —N(R7)C(O)R3, —OC(O)R3,    -   —OR4, hydroxy-2-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,        pyridyl-1-4C-alkoxy, (1-4C-alkoxy-2-4C-alkoxy)-2-4C-alkoxy, and        phenyl-1-4C-alkoxy,    -   wherein each of said Har and Het is optionally substituted by        one or two substituents independently selected from R10,    -   in which-   each R3, R4, R5 and R6 may be the same or different and is each    independently selected from the group consisting of:    -   hydrogen, and 1-4C-alkyl,-   each R7 may be the same or different and is independently selected    from the group consisting of:    -   hydrogen, and 1-4C-alkyl,-   each R10 may be the same or different is independently selected from    the group consisting of:    -   1-4C-alkyl, halogen, trifluoromethyl, cyano,    -   1-4C-alkoxycarbonyl, carboxyl, and    -   hydroxyl,-   each Rba, Rbb, Rbc, Rca and Rcb may be the same or different and is    each independently selected from the group consisting of:    -   1-4C-alkyl, halogen, trifluoromethyl, cyano,    -   1-4C-alkoxycarbonyl, carboxyl, and    -   hydroxyl,-   each Har is the same or different and is independently-   either    -   a 5-membered monocyclic heteroaryl radical comprising one to        four heteroatoms independently selected from nitrogen, oxygen        and sulphur,    -   such as e.g. any one selected from furanyl, thiophenyl,        pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,        imidazolyl, pyrazolyl, triazolyl, thiadiazolyl and oxadiazolyl,    -   whereby said Har radical is attached to the parent molecular        group via a ring carbon or ring nitrogen atom,-   or    -   a 6-membered monocyclic heteroaryl radical comprising one or two        nitrogen atoms, such as e.g. any one selected from pyridinyl,        pyrazinyl, pyridazinyl and pyrimidinyl, whereby said Har radical        is attached to the parent molecular group via a ring carbon        atom,-   Het is a 3- to 7-membered monocyclic fully saturated heterocyclic    ring comprising one or two heteroatoms independently selected from    nitrogen, oxygen and sulphur,    -   such as e.g. any one selected from aziridinyl, azetidinyl,        pyrrolidinyl, piperidinyl,-   homopiperidinyl,    -   pyrazolidinyl, imidazolidinyl, piperazinyl, homopiperazinyl,        morpholinyl and thiomorpholinyl,    -   whereby said Het radical is attached to the parent molecular        group via a ring carbon or ring nitrogen atom;-   under the proviso, that-   (6-acetyl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide-   is thereof disclaimed;-   and the salts thereof.

In another embodiment, compounds according to aspect a of the presentinvention more worthy to be mentioned include those compounds of formulaI as defined at the outset, or, particularly, of formulae Ia, Ib, Ic orId as shown below,

wherein

-   Ra is —C(O)R1, in which-   R1 is 1-4C-alkyl, or 1-C-alkyl substituted by one or two    substituents independently selected from R2,-   Rb is -T-Q, in which-   T is 1-6C-alkylene or 3-7C-cycloalkylene, and-   either-   Q is optionally substituted by Rba and/or Rbb and/or Rbc, and is    phenyl,-   or-   Q is optionally substituted by Rca and/or Rcb, and is Har,-   or-   Q is attached via a carbon atom of the benzene ring to the parent    molecular group, and is 1,3-benzodioxolyl,    2,2-difluoro-1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl,    2,3-dihydrobenzofuranyl, chromenyl or chromanyl,-   or-   Q is tetrahyrofuranyl,-   or-   Q is 3-7C-cycloalkyl,    wherein-   each R2 may be the same or different and is independently selected    from the group consisting of:    -   Har, Het,    -   —C(O)R3, —C(O)OR4, —C(O)N(R5)R6,    -   —N(R7)C(O)R3, —OC(O)R3,    -   —OR4, hydroxy-2-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,        pyridyl-1-4C-alkoxy, (1-4C-alkoxy-2-4C-alkoxy)-2-4C-alkoxy, and        phenyl-1-4C-alkoxy,    -   wherein said Har is optionally substituted by one or two        substituents independently selected from R10,    -   in which-   each R3, R4, R5 and R6 may be the same or different and is each    independently selected from the group consisting of:    -   hydrogen, and 1-4C-alkyl,-   each R7 may be the same or different and is independently selected    from the group consisting of:    -   hydrogen, and 1-4C-alkyl,-   each R10 may be the same or different is independently selected from    the group consisting of:    -   1-4C-alkyl, halogen, trifluoromethyl, cyano,    -   1-4C-alkoxycarbonyl, carboxyl, and    -   hydroxyl,-   each Rba, Rbb, Rbc, Rca and Rcb may be the same or different and is    each independently selected from the group consisting of:    -   1-4C-alkyl, halogen, trifluoromethyl, cyano,    -   1-4C-alkoxycarbonyl, carboxyl, and    -   hydroxyl,-   each Har is the same or different and is independently-   either    -   a 5-membered monocyclic heteroaryl radical comprising one to        four heteroatoms independently selected from nitrogen, oxygen        and sulphur,    -   such as e.g. any one selected from furanyl, thiophenyl,        pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,        imidazolyl, pyrazolyl, triazolyl, thiadiazolyl and oxadiazolyl,    -   whereby said Har radical is attached to the parent molecular        group via a ring carbon or ring nitrogen atom,-   or    -   a 6-membered monocyclic heteroaryl radical comprising one or two        nitrogen atoms, such as e.g. any one selected from pyridinyl,        pyrazinyl, pyridazinyl and pyrimidinyl,    -   whereby said Har radical is attached to the parent molecular        group via a ring carbon atom,-   Het is a 3- to 7-membered monocyclic fully saturated heterocyclic    ring comprising one or two heteroatoms independently selected from    nitrogen, oxygen and sulphur,    -   such as e.g. any one selected from aziridinyl, azetidinyl,        pyrrolidinyl, piperidinyl,-   homopiperidinyl,    -   pyrazolidinyl, imidazolidinyl, piperazinyl, homopiperazinyl,        morpholinyl and thiomorpholinyl,    -   whereby said Het radical is attached to the parent molecular        group via a ring carbon or ring nitrogen atom;-   under the proviso, that-   (6-acetyl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide-   is thereof disclaimed;-   and the salts thereof.

Compounds according to aspect a of the present invention in particularworthy to be mentioned include those compounds of formulae Ia, Ib, Ic,Id or Id′ as shown below

wherein

-   Ra is —C(O)R1, in which-   R1 is 1-4C-alkyl, 1-4C-alkyl substituted by one substituent selected    from R2, or 3-4C-alkyl substituted by two hydroxyl radicals on    different carbon atoms, and-   either-   Q is optionally substituted by Rba and/or Rbb, and is phenyl,-   or-   Q is optionally substituted by Rca and/or Rcb, and is pyridinyl,    furanyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl or    imidazolyl,-   or-   Q is attached via a carbon atom of the benzene ring to the parent    molecular group, and is 1,3-benzodioxolyl,    2,2-difluoro-1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl,    2,3-dihydrobenzofuranyl, chromenyl or chromanyl,-   or-   Q is attached via a carbon atom of the benzene ring to the parent    molecular group, and is benzofuranyl,-   or-   Q is tetrahyrofuranyl,-   or-   Q is 3-7C-cycloalkyl,    wherein-   each R2 may be the same or different and is independently selected    from the group consisting of:    -   Har, morpholino, 4-methyl-piperazin-1-yl,    -   —C(O)R3, —C(O)OR4, —C(O)N(R5)R6, —N(R7)C(O)R3, —OC(O)R3,    -   —OR4, hydroxy-2-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,        pyridyl-1-4C-alkoxy, phenyl-1-4C-alkoxy, and        (1-4C-alkoxy-2-4C-alkoxy)-2-4C-alkoxy,    -   wherein said Har may be optionally substituted by one or two        substituents independently selected from R10,    -   in which-   each R3, R4, R5 and R6 may be the same or different and is each    independently selected from the group consisting of:    -   hydrogen, and 1-4C-alkyl,-   R7 is hydrogen,-   either-   Har is bonded to the parent molecular group via a ring carbon atom    or a ring nitrogen atom, and is imidazolyl, pyrazolyl or triazolyl,-   or-   Har is bonded to the parent molecular group via a ring carbon atom,    and is pyridinyl, pyrazinyl or pyrimidinyl,-   R10 is 1-4C-alkyl,-   each Rba and Rbb may be the same or different and is each    independently selected from the group consisting of:    -   1-4C-alkyl, fluorine, chlorine, bromine, trifluoromethyl, cyano,        and hydroxyl,-   each Rca and Rcb may be the same or different and is each    independently selected from the group consisting of:    -   1-4C-alkyl, fluorine, chlorine, trifluoromethyl, and cyano;-   under the proviso, that-   (6-acetyl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide-   is thereof disclaimed;-   and the salts thereof.

In another embodiment, compounds according to aspect a of the presentinvention in particular worthy to be mentioned include those compoundsof formulae Ia, Ib, Ic or Id as shown below

wherein

-   Ra is —C(O)R1, in which-   R1 is 1-4C-alkyl, 1-4C-alkyl substituted by one substituent selected    from R2, or 3-4C-alkyl substituted by two hydroxyl radicals on    different carbon atoms, and-   either-   Q is optionally substituted by Rba and/or Rbb, and is phenyl,-   or-   Q is optionally substituted by Rca and/or Rcb, and is pyridinyl,    furanyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl or    imidazolyl,-   or-   Q is attached via a carbon atom of the benzene ring to the parent    molecular group, and is 1,3-benzodioxolyl,    2,2-difluoro-1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl,    2,3-dihydrobenzofuranyl, chromenyl or chromanyl,-   or-   Q is tetrahyrofuranyl,-   or-   Q is 3-7C-cycloalkyl,    wherein-   each R2 may be the same or different and is independently selected    from the group consisting of:    -   pyridinyl, pyrimidinyl, pyrazinyl, triazol-1-yl, imidazol-1-yl,        pyrazol-1-yl, morpholino, 1N-(1-4C-alkyl)-imidazolyl,        1N-(1-4C-alkyl)-pyrazolyl,    -   —C(O)R3, —C(O)OR4, —C(O)N(R5)R6,    -   —N(R7)C(O)R3, —OC(O)R3,    -   —OR4, hydroxy-2-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,        pyridyl-1-4C-alkoxy, and (1-4C-alkoxy-2-4C-alkoxy)-2-4C-alkoxy,    -   in which-   each R3, R4, R5 and R6 may be the same or different and is each    independently selected from the group consisting of:    -   hydrogen, and 1-4C-alkyl,-   R7 is hydrogen,-   each Rba and Rbb may be the same or different and is each    independently selected from the group consisting of:    -   1-4C-alkyl, fluorine, chlorine, bromine, trifluoromethyl, cyano,        and hydroxyl,-   each Rca and Rcb may be the same or different and is each    independently selected from the group consisting of:    -   1-4C-alkyl, fluorine, chlorine, trifluoromethyl, and cyano;-   under the proviso, that-   (6-acetyl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide-   is thereof disclaimed;-   and the salts thereof.

In one embodiment of aspect a (embodiment a1), compounds according toaspect a of the present invention in more particular worthy to bementioned include those compounds of formula Ia, Ib or Ic as shown below

wherein

-   Ra is —C(O)R1, in which-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl,    -   or    -   1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is        substituted by one substituent selected from R2,    -   or    -   1-2C-alkyl, such as e.g. methyl or ethyl, which is substituted        by 2,2-dimethyl-[1,3]dioxolan-4-yl,    -   or    -   3-4C-alkyl, such as e.g. propyl or butyl, which is substituted        by two hydroxyl radicals on different carbon atoms, and-   either-   Q is optionally substituted by Rba and/or Rbb, and is phenyl,-   or-   Q is optionally substituted by Rca and/or Rcb, and is pyridinyl,    furanyl, thiophenyl or pyrazol-1-yl,-   or-   Q is 1,3-benzodioxol-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl,    2,2-difluoro-1,3-benzodioxol-5-yl, chromen-6-yl, chromen-7-yl,    chroman-6-yl, chroman-7-yl, 2,3-dihydrobenzofuran-5-yl, or    2,3-dihydrobenzofuran-6-yl,-   or-   Q is benzofuran-5-yl, or benzofuran-6-yl,-   or-   Q is tetrahydrofuranyl,-   or-   Q is 5-6C-cycloalkyl,    wherein-   each R2 may be the same or different and is independently selected    from the group consisting of:    -   pyridyl, pyrimidinyl, R201- and/or R202-substituted pyridyl,        R201- and/or R202-substituted pyrimidinyl, morpholino,        imidazol-1-yl, pyrazol-1-yl, mono- or di-(R201)-substituted        imidazol-1-yl, mono- or di-(R201)-substituted pyrazol-1-yl,        1N-(1-4C-alkyl)-imidazolyl, 1N-(1-4C-alkyl)-pyrazol-1-yl,        R201-substituted 1N-(1-4C-alkyl)-imidazolyl, R201-substituted        1N-(1-4C-alkyl)-pyrazol-1-yl, 1N—(H)-imidazolyl,        1N—(H)-pyrazol-1-yl, R201-substituted 1N—(H)-imidazolyl,        R201-substituted 1N—(H)-pyrazol-1-yl, —C(O)OR4, —OC(O)R3,    -   —OR4,    -   phenyl-1-2C-alkoxy such as e.g. benzyloxy,    -   1-2C-alkoxy-2-3C-alkoxy such as e.g. 2-methoxyethoxy, and    -   (1-2C-alkoxy-2-3C-alkoxy)-2-3C-alkoxy such as e.g.        2-(2-methoxyethoxy)-ethoxy,    -   in which-   R3 is 1-4C-alkyl such as e.g. methyl,-   each R4 may be the same or different and is independently selected    from the group consisting of:    -   hydrogen, and 1-4C-alkyl such as e.g. methyl or ethyl,-   R201 is 1-4C-alkyl such as e.g. methyl or ethyl,-   R202 is 1-4C-alkyl such as e.g. methyl or ethyl,-   each Rba and Rbb may be the same or different and is each    independently selected from the group consisting of:    -   methyl, ethyl, fluorine, chlorine, bromine, and trifluoromethyl,-   each Rca and Rcb may be the same or different and is each    independently selected from the group consisting of:    -   methyl, ethyl, fluorine, chlorine, and trifluoromethyl;-   in a particular subembodiment-   Q is unsubstituted, and is pyridinyl, e.g. pyridin-2-yl,    pyridin-3-yl or pyridin-4-yl, especially pyridin-2-yl or    pyridin-3-yl,-   in another particular subembodiment-   Q is unsubstituted, and is furanyl, e.g. furan-2-yl or furan-3-yl,    especially furan-2-yl,-   in another particular subembodiment-   Q is unsubstituted, and is thiophenyl, e.g. thiophen-2-yl or    thiophen-3-yl, especially thiophen-2-yl,-   in another particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   in another particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   in another particular subembodiment-   Q is 2-(Rca)-furan-3-yl, 5-(Rca)-furan-3-yl, or, especially,    5-(Rca)-furan-2-yl, in which-   Rca is methyl or chlorine,-   in another particular subembodiment-   Q is 5-(Rca)-3-(Rcb)-furan-2-yl, 2-(Rca)-4-(Rcb)-furan-3-yl,    2-(Rca)-5-(Rcb)-furan-3-yl, 2-(Rcb)-5-(Rca)-furan-3-yl,    5-(Rca)-4-(Rcb)-furan-3-yl, or, especially,    5-(Rca)-4-(Rcb)-furan-2-yl, in which-   Rca is methyl or chlorine,-   Rcb is methyl,-   in another particular subembodiment-   Q is 2-(Rca)-thiophen-3-yl, 5-(Rca)-thiophen-3-yl, or, especially,    5-(Rca)-thiophen-2-yl, in which-   Rca is methyl or chlorine,-   in another particular subembodiment-   Q is 5-(Rca)-3-(Rcb)-thiophen-2-yl, 2-(Rca)-4-(Rcb)-thiophen-3-yl,    2-(Rca)-5-(Rcb)-thiophen-3-yl,    -   2-(Rcb)-5-(Rca)-thiophen-3-yl, 5-(Rca)-4-(Rcb)-thiophen-3-yl,        or, especially, 5-(Rca)-4-(Rcb)-thiophen-2-yl, in which-   Rca is methyl or chlorine,-   Rcb is methyl;-   in a more particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl or pyridin-3-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl,-   in another more particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine,-   in another more particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine;-   under theproviso, that-   (6-acetyl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide-   is thereof disclaimed;-   and the salts thereof.

In another embodiment of aspect a (embodiment a2), compounds accordingto aspect a of the present invention in more particular worthy to bementioned include those compounds of formula Ia as shown below

wherein

-   Ra is —C(O)R1, in which-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl,    -   or    -   1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is        substituted by one substituent selected from R2,    -   or    -   3-4C-alkyl, such as e.g. propyl or butyl, which is substituted        by two hydroxyl radicals on different carbon atoms, and-   either-   Q is optionally substituted by Rba and/or Rbb, and is phenyl,-   or-   Q is optionally substituted by Rca and/or Rcb, and is pyridinyl,    furanyl, thiophenyl or pyrazol-1-yl,-   or-   Q is 1,3-benzodioxol-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl,    2,2-difluoro-1,3-benzodioxol-5-yl, chromen-6-yl, chromen-7-yl,    chroman-yl, chroman-7-yl, 2,3-dihydrobenzofuran-5-yl, or    2,3-dihydrobenzofuran-6-yl,-   or-   Q is tetrahydrofuranyl,-   or-   Q is 5-6C-cycloalkyl,    wherein-   each R2 may be the same or different and is independently selected    from the group consisting of:    -   pyridinyl, morpholino, imidazol-1-yl, pyrazol-1-yl,    -   —C(O)OR4, —OC(O)R3,    -   —OR4,    -   1-2C-alkoxy-2-3C-alkoxy such as e.g. 2-methoxyethoxy, and    -   (1-2C-alkoxy-2-3C-alkoxy)-2-3C-alkoxy such as e.g.        2-(2-methoxyethoxy)-ethoxy,    -   in which-   R3 is 1-4C-alkyl such as e.g. methyl,-   each R4 may be the same or different and is independently selected    from the group consisting of:    -   hydrogen, and 1-4C-alkyl such as e.g. methyl or ethyl,-   each Rba and Rbb may be the same or different and is each    independently selected from the group consisting of:    -   methyl, ethyl, fluorine, chlorine, bromine, and trifluoromethyl,-   Rca is methyl,-   Rcb is methyl;-   in a particular subembodiment-   Q is unsubstituted, and is pyridinyl, e.g. pyridin-2-yl,    pyridin-3-yl or pyridin-4-yl, especially pyridin-2-yl or    pyridin-3-yl,-   in another particular subembodiment-   Q is unsubstituted, and is furanyl, e.g. furan-2-yl or furan-3-yl,    especially furan-2-yl,-   in another particular subembodiment-   Q is unsubstituted, and is thiophenyl, e.g. thiophen-2-yl or    thiophen-3-yl, especially thiophen-2-yl,-   in another particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   in another particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   in another particular subembodiment-   Q is 2-(Rca)-furan-3-yl, 5-(Rca)-furan-3-yl, or, especially,    5-(Rca)-furan-2-yl, in which-   Rca is methyl,-   in another particular subembodiment-   Q is 5-(Rca)-3-(Rcb)-furan-2-yl, 2-(Rca)-4-(Rcb)-furan-3-yl,    2-(Rca)-5-(Rcb)-furan-3-yl, 2-(Rcb)-5-(Rca)-furan-3-yl,    5-(Rca)-4-(Rcb)-furan-3-yl, or, especially,    5-(Rca)-4-(Rcb)-furan-2-yl, in which-   Rca is methyl,-   Rcb is methyl,-   in another particular subembodiment-   Q is 2-(Rca)-thiophen-3-yl, 5-(Rca)-thiophen-3-yl, or, especially,    5-(Rca)-thiophen-2-yl, in which-   Rca is methyl,-   in another particular subembodiment-   Q is 5-(Rca)-3-(Rcb)-thiophen-2-yl, 2-(Rca)-4-(Rcb)-thiophen-3-yl,    2-(Rca)-5-(Rcb)-thiophen-3-yl, 2-(Rcb)-5-(Rca)-thiophen-3-yl,    5-(Rca)-4-(Rcb)-thiophen-3-yl, or, especially,    5-(Rca)-4-(Rcb)-thiophen-2-yl, in which-   Rca is methyl,-   Rcb is methyl;-   in a more particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl or pyridin-3-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl,-   in another more particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine,-   in another more particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine;-   under theproviso, that-   (6-acetyl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide-   is thereof disclaimed;-   and the salts thereof.

In a more detailed embodiment of aspect a (aspect a1′i), compoundsaccording to aspect a of the present invention in further moreparticular worthy to be mentioned include those compounds of formula Ia,Ib or Ic as shown below

wherein

-   Ra is —C(O)R1, in which-   either-   R1 is methyl, ethyl or propyl,-   or-   R1 is (R2)-methyl, 2-(R2)-ethyl, or 3-(R2)-propyl,-   or-   R1 is 2,3-dihydroxypropyl, and-   either-   Q is unsubstituted, and is phenyl,-   or-   Q is unsubstituted, and is pyridinyl, furanyl or thiophenyl,-   or-   Q is substituted by Rba and/or Rbb, and is phenyl,-   or-   Q is substituted by Rca and/or Rcb, and is pyridinyl, furanyl or    thiophenyl,    wherein-   each R2 may be the same or different and is independently selected    from the group consisting of:    -   pyridyl, pyrimidinyl, methyl-substituted pyridyl, imidazol-1-yl,        mono- or di-methyl-substituted imidazol-1-yl, carboxyl,        methoxycarbonyl, hydroxyl, methylcarbonyloxy, methoxy, ethoxy,        benzyloxy, and 2-methoxyethoxy,-   each Rba and Rbb may be the same or different and is each    independently selected from the group consisting of:    -   methyl, ethyl, fluorine and chlorine,-   each Rca and Rcb may be the same or different and is each    independently selected from the group consisting of:    -   methyl, ethyl and chlorine;-   in a particular subembodiment-   Q is unsubstituted, and is pyridinyl, e.g. pyridin-2-yl,    pyridin-3-yl or pyridin-4-yl, especially pyridin-2-yl or    pyridin-3-yl,-   in another particular subembodiment-   Q is unsubstituted, and is furanyl, e.g. furan-2-yl or furan-3-yl,    especially furan-2-yl,-   in another particular subembodiment-   Q is unsubstituted, and is thiophenyl, e.g. thiophen-2-yl or    thiophen-3-yl, especially thiophen-2-yl,-   in another particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   in another particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   in another particular subembodiment-   Q is 5-(Rca)-furan-3-yl, or, especially, 5-(Rca)-furan-2-yl, in    which-   Rca is methyl or chlorine,-   in another particular subembodiment-   Q is 5-(Rca)-4-(Rcb)-furan-3-yl, or, especially,    5-(Rca)-4-(Rcb)-furan-2-yl, in which-   Rca is methyl or chlorine,-   Rcb is methyl,-   in another particular subembodiment-   Q is 5-(Rca)-thiophen-3-yl, or, especially, 5-(Rca)-thiophen-2-yl,    in which-   Rca is methyl or chlorine;-   in a more particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl or pyridin-3-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl,-   in another more particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine,-   in another more particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine;-   in a further more particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl,-   in another further more particular subembodiment-   Q is unsubstituted, and is pyridin-3-yl,-   in another further more particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another further more particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl;-   under theproviso, that-   (6-acetyl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide-   is thereof disclaimed;-   and the salts thereof.

Yet in a more detailed embodiment of aspect a (aspect a1′ii), compoundsaccording to aspect a of the present invention in further moreparticular worthy to be mentioned include those compounds of formula Ia,Ib or Ic as shown below

wherein

-   Ra is —C(O)R1, in which-   either-   R1 is methyl, ethyl or propyl,-   or-   R1 is (R2)-methyl, 2-(R2)-ethyl, or 3-(R2)-propyl,-   or-   R1 is 2,3-dihydroxypropyl, and-   either-   Q is unsubstituted, and is phenyl,-   or-   Q is unsubstituted, and is pyridinyl, furanyl or thiophenyl,-   or-   Q is substituted by Rba and/or Rbb, and is phenyl,-   or-   Q is substituted by Rca and/or Rcb, and is pyridinyl, furanyl or    thiophenyl,-   or-   Q is cyclohexyl or cyclopentyl,    wherein-   each R2 may be the same or different and is independently selected    from the group consisting of:    -   pyridyl, pyrimidinyl, methyl-substituted pyridyl, imidazol-1-yl,        mono- or di-methyl-substituted imidazol-1-yl,        1N-methyl-imidazolyl, carboxyl, methoxycarbonyl, hydroxyl,        methylcarbonyloxy, methoxy, ethoxy, benzyloxy, and        2-methoxyethoxy,-   each Rba and Rbb may be the same or different and is each    independently selected from the group consisting of:    -   methyl, ethyl, fluorine and chlorine,-   each Rca and Rcb may be the same or different and is each    independently selected from the group consisting of:    -   methyl, ethyl and chlorine;-   in a particular subembodiment-   Q is unsubstituted, and is phenyl,-   in another particular subembodiment-   Q is unsubstituted, and is pyridinyl, e.g. pyridin-2-yl,    pyridin-3-yl or pyridin-4-yl, especially pyridin-2-yl or    pyridin-3-yl,-   in another particular subembodiment-   Q is unsubstituted, and is furanyl, e.g. furan-2-yl or furan-3-yl,    especially furan-2-yl,-   in another particular subembodiment-   Q is unsubstituted, and is thiophenyl, e.g. thiophen-2-yl or    thiophen-3-yl, especially thiophen-2-yl,-   in another particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   in another particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   in another particular subembodiment-   Q is 5-(Rca)-furan-3-yl, or, especially, 5-(Rca)-furan-2-yl, in    which-   Rca is methyl or chlorine,-   in another particular subembodiment-   Q is 5-(Rca)-4-(Rcb)-furan-3-yl, or, especially,    5-(Rca)-4-(Rcb)-furan-2-yl, in which-   Rca is methyl or chlorine,-   Rcb is methyl,-   in another particular subembodiment-   Q is 5-(Rca)-thiophen-3-yl, or, especially, 5-(Rca)-thiophen-2-yl,    in which-   Rca is methyl or chlorine,-   in another particular subembodiment-   Q is cyclohexyl or cyclopentyl;-   in a more particular subembodiment-   Q is unsubstituted, and is phenyl,-   in another more particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl or pyridin-3-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl,-   in another more particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine,-   in another more particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine,-   in another more particular subembodiment-   Q is cyclohexyl or cyclopentyl;-   in a further more particular subembodiment-   Q is unsubstituted, and is phenyl,-   in another further more particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl,-   in another further more particular subembodiment-   Q is unsubstituted, and is pyridin-3-yl,-   in another further more particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another further more particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl,-   in another further more particular subembodiment-   Q is cyclohexyl;-   under theproviso, that-   (6-acetyl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide-   is thereof disclaimed;-   and the salts thereof.

In another more detailed embodiment of aspect a (aspect a2′), compoundsaccording to aspect a of the present invention in further moreparticular worthy to be mentioned include those compounds of formula Iaas shown below

wherein

-   Ra is —C(O)R1, in which-   either-   R1 is methyl, ethyl or propyl,-   or-   R1 is (R2)-methyl, 2-(R2)-ethyl, or 3-(R2)-propyl,-   or-   R1 is 2,3-dihydroxypropyl, and-   either-   Q is unsubstituted, and is phenyl,-   or-   Q is unsubstituted, and is pyridinyl, furanyl or thiophenyl,-   or-   Q is substituted by Rba and/or Rbb, and is phenyl,    wherein-   each R2 may be the same or different and is independently selected    from the group consisting of:    -   pyridinyl, methoxycarbonyl, methylcarbonyloxy, methoxy, ethoxy,        and 2-methoxyethoxy,-   each Rba and Rbb may be the same or different and is each    independently selected from the group consisting of:    -   methyl, ethyl, fluorine, bromine, and chlorine;-   in a particular subembodiment-   Q is unsubstituted, and is pyridinyl, e.g. pyridin-2-yl,    pyridin-3-yl or pyridin-4-yl, especially pyridin-2-yl or    pyridin-3-yl,-   in another particular subembodiment-   Q is unsubstituted, and is furanyl, e.g. furan-2-yl or furan-3-yl,    especially furan-2-yl,-   in another particular subembodiment-   Q is unsubstituted, and is thiophenyl, e.g. thiophen-2-yl or    thiophen-3-yl, especially thiophen-2-yl,-   in another particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   in another particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine;-   in a more particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl or pyridin-3-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl,-   in another more particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine,-   in another more particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine;-   in a further more particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl,-   in another further more particular subembodiment-   Q is unsubstituted, and is pyridin-3-yl,-   in another further more particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another further more particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl;-   under theproviso, that-   (6-acetyl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide-   is thereof disclaimed;-   and the salts thereof.

Compounds according to aspect a of the present invention to beemphasized include those compounds of formula Ia or Ic as shown below

wherein

-   Ra is —C(O)R1, in which-   either-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is pyridyl,-   or-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is methoxy,-   or-   R1 is (2-methoxyethoxy)-methyl,-   or-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is imidazol-1-yl;    and wherein-   either-   Q is unsubstituted, and is pyridinyl, e.g. pyridin-2-yl,    pyridin-3-yl or pyridin-4-yl, especially pyridin-2-yl or    pyridin-3-yl,-   or-   Q is unsubstituted, and is furanyl, e.g. furan-2-yl or furan-3-yl,    especially furan-2-yl,-   or-   Q is unsubstituted, and is thiophenyl, e.g. thiophen-2-yl or    thiophen-3-yl, especially thiophen-2-yl,-   or-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   or-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   or-   Q is 5-(Rca)-furan-2-yl, in which-   Rca is methyl or chlorine,-   or-   Q 5-(Rca)-4-(Rcb)-furan-2-yl, in which-   Rca is methyl or chlorine,-   Rcb is methyl,-   or-   Q is 5-(Rca)-thiophen-2-yl, in which-   Rca is methyl or chlorine;-   in a particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl,-   in another particular subembodiment-   Q is unsubstituted, and is pyridin-3-yl,-   in another particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl,-   in another particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine,-   in another particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine;-   in a more particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is pyridin-3-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl;-   and the salts thereof.

Yet compounds according to aspect a of the present invention to beemphasized include those compounds of formula Ia, Ib or Ic as shownbelow

wherein

-   Ra is —C(O)R1, in which-   either-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is pyridyl,-   or-   R1 is (R2)-methyl, in which-   R2 is 1N-methyl-imidazolyl,-   or-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is hydroxyl or methoxy,-   or-   R1 is (2-methoxyethoxy)-methyl,-   or-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is imidazol-1-yl, or mono- or di-methyl-substituted    imidazol-1-yl;    and wherein-   either-   Q is unsubstituted, and is phenyl,-   or-   Q is unsubstituted, and is pyridinyl, e.g. pyridin-2-yl,    pyridin-3-yl or pyridin-4-yl, especially pyridin-2-yl or    pyridin-3-yl,-   or-   Q is unsubstituted, and is furanyl, e.g. furan-2-yl or furan-3-yl,    especially furan-2-yl,-   or-   Q is unsubstituted, and is thiophenyl, e.g. thiophen-2-yl or    thiophen-3-yl, especially thiophen-2-yl,-   or-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   or-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   or-   Q is 5-(Rca)-furan-2-yl, in which-   Rca is methyl or chlorine,-   or-   Q 5-(Rca)-4-(Rcb)-furan-2-yl, in which-   Rca is methyl or chlorine,-   Rcb is methyl,-   or-   Q is 5-(Rca)-thiophen-2-yl, in which-   Rca is methyl or chlorine,-   or-   Q is cyclohexyl or cyclopentyl;-   in a particular subembodiment-   Q is unsubstituted, and is phenyl,-   in another particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl,-   in another particular subembodiment-   Q is unsubstituted, and is pyridin-3-yl,-   in another particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl,-   in another particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine,-   in another particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine,-   in another particular subembodiment-   Q is cyclohexyl or cyclopentyl;-   in a more particular subembodiment-   Q is unsubstituted, and is phenyl,-   in another more particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is pyridin-3-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl,-   in another more particular subembodiment-   Q is cyclohexyl;-   and the salts thereof.

Compounds according to aspect a of the present invention to be moreemphasized include those compounds of formula Ia or Ic as shown below

wherein

-   Ra is —C(O)R1, in which-   either-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is pyridyl,-   or-   R1 is 2-(R2)-ethyl, in which-   R2 is imidazol-1-yl;    and wherein-   either-   Q is unsubstituted, and is pyridinyl, e.g. pyridin-2-yl,    pyridin-3-yl or pyridin-4-yl, especially pyridin-2-yl or    pyridin-3-yl,-   or-   Q is unsubstituted, and is furanyl, e.g. furan-2-yl or furan-3-yl,    especially furan-2-yl,-   or-   Q is unsubstituted, and is thiophenyl, e.g. thiophen-2-yl or    thiophen-3-yl, especially thiophen-2-yl,-   or-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   or-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   or-   Q is 5-(Rca)-furan-2-yl, in which-   Rca is methyl or chlorine,-   or-   Q is 5-(Rca)-4-(Rcb)-furan-2-yl, in which-   Rca is methyl or chlorine,-   Rcb is methyl,-   or-   Q is 5-(Rca)-thiophen-2-yl, in which-   Rca is methyl or chlorine;-   in a particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl,-   in another particular subembodiment-   Q is unsubstituted, and is pyridin-3-yl,-   in another particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl,-   in another particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine,-   in another particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine;-   in a more particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is pyridin-3-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is furan-2-yl;-   and the salts thereof.

Yet compounds according to aspect a of the present invention to be moreemphasized include those compounds of formula Ia, Ib or Ic as shownbelow

wherein

-   Ra is —C(O)R1, in which-   either-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl,-   or-   R1 is (R2)-methyl, in which-   R2 is 1-methyl-imidazol-2-yl or 1-methyl-imidazol-5-yl,-   or-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is hydroxyl,-   or-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is imidazol-1-yl, 2-methyl-imidazol-1-yl, 4-methyl-imidazol-1-yl    or 2,4-dimethyl-imidazol-1-yl;    and wherein-   either-   Q is unsubstituted, and is phenyl,-   or-   Q is unsubstituted, and is pyridinyl, e.g. pyridin-2-yl,    pyridin-3-yl or pyridin-4-yl, especially pyridin-2-yl or    pyridin-3-yl,-   or-   Q is unsubstituted, and is furanyl, e.g. furan-2-yl or furan-3-yl,    especially furan-2-yl,-   or-   Q is unsubstituted, and is thiophenyl, e.g. thiophen-2-yl or    thiophen-3-yl, especially thiophen-2-yl,-   or-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   or-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, ethyl, chlorine or fluorine,-   or-   Q is 5-(Rca)-furan-2-yl, in which-   Rca is methyl or chlorine,-   or-   Q is 5-(Rca)-4-(Rcb)-furan-2-yl, in which-   Rca is methyl or chlorine,-   Rcb is methyl,-   or-   Q is 5-(Rca)-thiophen-2-yl, in which-   Rca is methyl or chlorine,-   or-   Q is cyclohexyl or cyclopentyl;-   in a particular subembodiment-   Q is unsubstituted, and is phenyl,-   in another particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl,-   in another particular subembodiment-   Q is unsubstituted, and is pyridin-3-yl,-   in another particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another particular subembodiment-   Q is unsubstituted, and is thiophen-2-yl,-   in another particular subembodiment-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine,-   in another particular subembodiment-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, chlorine or fluorine,-   in another particular subembodiment-   Q is cyclohexyl; in a more particular subembodiment-   Q is unsubstituted, and is phenyl,-   in another more particular subembodiment-   Q is unsubstituted, and is pyridin-2-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is pyridin-3-yl,-   in another more particular subembodiment-   Q is unsubstituted, and is furan-2-yl,-   in another more particular subembodiment-   Q is cyclohexyl;-   and the salts thereof.

Compounds according to aspect a of the present invention to be furthermore emphasized include those compounds of formula Ia, Ib or Ic as shownbelow

wherein

-   Ra is —C(O)R1, in which-   either-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl,-   or-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is hydroxyl,-   or-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is imidazol-1-yl;    and wherein-   either-   Q is unsubstituted, and is phenyl,-   or-   Q is unsubstituted, and is pyridin-2-yl,-   or-   Q is unsubstituted, and is pyridin-3-yl,-   or-   Q is unsubstituted, and is furan-2-yl,-   or-   Q is cyclohexyl;    and the salts thereof.

Compounds according to aspect a of the present invention to be inparticular emphasized include those compounds of formula Ia, Ib or Ic asshown below

wherein

-   Ra is —C(O)R1, in which-   either-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl,-   or-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is imidazol-1-yl;    and wherein-   either-   Q is unsubstituted, and is phenyl,-   or-   Q is unsubstituted, and is pyridin-2-yl,-   or

Q is unsubstituted, and is pyridin-3-yl,

-   or-   Q is unsubstituted, and is furan-2-yl,-   or-   Q is cyclohexyl;    and the salts thereof.

Compounds according to aspect a of the present invention to be in moreparticular emphasized include those compounds of formula Ia, Ib or Ic asshown below

wherein

-   Ra is —C(O)R1, in which-   either-   R1 is (R2)-methyl, or 2-(R2)-ethyl, in which-   R2 is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl;    and wherein-   either-   Q is unsubstituted, and is phenyl,-   or-   Q is unsubstituted, and is pyridin-2-yl,-   or-   Q is unsubstituted, and is pyridin-3-yl,-   or-   Q is unsubstituted, and is furan-2-yl,-   or-   Q is cyclohexyl;-   and the salts thereof.

In the compounds of formula I according to the present invention, thesignificances mentioned in the following details/subdetails and/orvariants/subvariants are of concern individually or in any possiblesingle or multiple combination thereof:

A first embodimental detail (detail a) of the compounds of formula Iaccording to this invention includes those compounds of formula I,

in which

-   Ra is —C(O)R1, in which-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl, propyl or butyl.

A second embodimental detail (detail b) of the compounds of formula Iaccording to this invention includes those compounds of formula I,

in which

-   Ra is —C(O)R1, in which-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 has one of the meanings as defined in the compounds mentioned    above.

A subdetail (detail b1) of the compounds according to detail b of thisinvention include those compounds of formula I,

in which

-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    (1-4C-alkoxy-2-4C-alkoxy)-2-4C-alkoxy, hydroxyl,    1-4C-alkoxycarbonyl, phenyl-1-4C-alkoxy, 1-4C-alkylcarbonyloxy,    carboxyl, mono- or di-1-4C-alkylaminocarbonyl, carbamoyl,    1-4C-alkylcarbonylamino, 1-4C-alkylcarbonyl, or Har, in which-   Har has one of the meanings as defined in the compounds mentioned    above.

A further subdetail (detail b2) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    (1-4C-alkoxy-2-4C-alkoxy)-2-4C-alkoxy, hydroxyl,    1-4C-alkoxycarbonyl, phenyl-1-4C-alkoxy, 1-4C-alkylcarbonyloxy,    carboxyl, mono- or di-1-4C-alkylaminocarbonyl, carbamoyl, or    1-4C-alkylcarbonylamino.

A further subdetail (detail b3) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 is 1-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,    (1-4C-alkoxy-2-4C-alkoxy)-2-4C-alkoxy, hydroxyl,    1-4C-alkoxycarbonyl, phenyl-1-4C-alkoxy, 1-4C-alkylcarbonyloxy, or    carboxyl.

A further subdetail (detail b4) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 is 1-2C-alkoxy, 1-2C-alkoxy-ethoxy, (1-2C-alkoxy-ethoxy)-ethoxy,    hydroxyl, 1-2C-alkoxycarbonyl, 1-2C-alkylcarbonyloxy, or carboxyl.

A further subdetail (detail b5) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 is Har, in which-   Har is optionally substituted by one or two substituents    independently selected from R10 as defined in the compounds    mentioned above, and is    -   a 5-membered monocyclic heteroaryl radical comprising one to        four heteroatoms independently selected from nitrogen, oxygen        and sulphur, such as e.g. any one selected from furanyl,        thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,        isothiazolyl, imidazolyl, pyrazolyl, triazolyl, thiadiazolyl and        oxadiazolyl,-   whereby said Har radical is attached to the adjacent 1-4C-alkyl    radical via a ring carbon or ring nitrogen atom.

A further subdetail (detail b6) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 is Har, in which-   Har is optionally substituted by one or two substituents    independently selected from R10 as defined in the compounds    mentioned above, and is    -   a 6-membered monocyclic heteroaryl radical comprising one or two        nitrogen atoms, such as e.g. any one selected from pyridinyl,        pyrazinyl, pyridazinyl and pyrimidinyl,-   whereby said Har radical is attached to the adjacent 1-4C-alkyl    radical via a ring carbon atom.

A further subdetail (detail b7) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 is morpholino.

A further subdetail (detail b8) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 is Har, in which-   Har is optionally substituted by one or two substituents    independently selected from R10 as defined in the compounds    mentioned above, and is pyridinyl.

A further subdetail (detail b9) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 is Har, in which-   Har is optionally mono-substituted by R10, and is pyridinyl,    imidazolyl (e.g. imidazol-1-yl) or pyrazolyl (e.g. pyrazol-1-yl), in    which-   R10 is 1-4C-alkyl,-   such as e.g.-   Har is pyridinyl, imidazol-1-yl, pyrazol-1-yl,    1N-(methyl)-imidazolyl or 1N-(methyl)-pyrazolyl.

A further subdetail (detail b10) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 is Har, in which-   Har is unsubstituted, and is pyridinyl.

A further subdetail (detail b11) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 is methoxy, ethoxy, hydroxyl, methoxycarbonyl, methylcarbonyloxy,    or 2-methoxyethoxy.

A further subdetail (detail b12) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 is 1-4C-alkoxy, such as e.g. methoxy or ethoxy, or hydroxyl.

Another subdetail (detail b12′) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 1-4C-alkyl, such as e.g. methyl, ethyl or propyl, which is    mono-substituted by R2, in which-   R2 is 2-methoxyethoxy.

A further subdetail (detail b13) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is (R2)-methyl, 2-(R2)-ethyl, or 3-(R2)-propyl, in which-   R2 is methoxy, ethoxy, hydroxyl, methylcarbonyloxy, or    2-methoxyethoxy.

A further subdetail (detail b14) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is (R2>methyl, or 2-(R2)-ethyl, in which-   R2 is methoxy, hydroxyl, or 2-methoxyethoxy.

A further subdetail (detail b15) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is propyl or butyl, each of which is bisubstituted by hydroxyl on    different carbon atoms, such as e.g. 2,3-dihydroxy-propyl.

A further subdetail (detail b16) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is (2-methoxyethoxy)methyl.

A further subdetail (detail b17) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is methoxymethyl.

A further subdetail (detail b18) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 2-methoxyethyl.

A further subdetail (detail b19) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is hydroxymethyl.

A further subdetail (detail b20) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 2-hydroxyethyl.

A further subdetail (detail b21) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is pyridylmethyl, 2-pyridylethyl, or 3-pyridylpropyl, such as    e.g. pyridin-2-yl-methyl, pyridin-3-yl-methyl, pyridin-4-yl-methyl,    2-(pyridin-2-yl)-ethyl, 2-(pyridin-3-yl)-ethyl or    2-(pyridin-4-yl)-ethyl.

A further subdetail (detail b22) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is (Raa)-methyl, or 2-(Raa)-ethyl, in which-   either-   Raa is pyridinyl,-   or-   Raa is methoxy, hydroxyl or 2-methoxyethoxy; especially, methoxy or    2-methoxyethoxy.

A further subdetail (detail b23) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is pyridylmethyl, such as e.g. pyridin-2-yl-methyl,    pyridin-3-yl-methyl or pyridin-4-yl-methyl.

A further subdetail (detail b24) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 2-pyridylethyl, such as e.g. 2-(pyridin-2-yl)-ethyl,    2-(pyridin-3-yl)-ethyl or 2-(pyridin-4-yl)-ethyl.

A further subdetail (detail b25) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is (R2)-methyl, 2-(R2)-ethyl or 3-(R2)-propyl, in which-   R2 is R201- and/or R202-substituted pyridyl, in which-   R201 is methyl,-   R202 is methyl.

A further subdetail (detail b26) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is (R2)-methyl, 2-(R2)-ethyl or 3-(R2)-propyl, in which-   R2 is imidazol-1-yl.

A further subdetail (detail b27) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is (R2)-methyl, 2-(R2)-ethyl or 3-(R2)-propyl, in which-   R2 is mono- or di-methyl-substituted imidazol-1-yl.

A further subdetail (detail b28) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is (Raa)-methyl, 2-(Raa)-ethyl or 3-(Raa)-propyl, in which-   Raa is 1N-methyl-imidazolyl.

A further subdetail (detail b29) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is (Raa)-methyl or 2-(Raa)-ethyl, in which-   Raa is mono- or di-methyl-substituted imidazol-1-yl, such as e.g.    2-methyl-imidazol-1-yl, 4-methyl-imidazol-1-yl or    2,4-dimethyl-imidazol-1-yl.

A further subdetail (detail b30) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 2-(2-methyl-imidazol-1-yl)-ethyl,    2-(4-methyl-imidazol-1-yl)-ethyl or    2-(2,4-dimethylimidazol-1-yl)-ethyl.

A further subdetail (detail b31) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is (2-methyl-imidazol-1-yl)-methyl,    (4-methyl-imidazol-1-yl)-methyl or    (2,4-dimethylimidazol-1-yl)-methyl.

A further subdetail (detail b32) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is (Raa)-methyl or 2-(Raa)-ethyl, in which-   Raa is 1N-methyl-imidazolyl, such as e.g. 1-methyl-imidazol-2-yl or    1-methyl-imidazol-5-yl.

A further subdetail (detail b33) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is (1-methyl-imidazol-2-yl)-methyl or    (1-methyl-imidazol-5-yl)-methyl.

A further subdetail (detail b34) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is imidazol-1-yl-methyl.

A further subdetail (detail b35) of the compounds according to detail bof this invention include those compounds of formula I,

in which

-   R1 is 2-(imidazol-1-yl)-ethyl.

A third embodimental detail (detail c) of the compounds of formula Iaccording to this invention includes those compounds of formula Ia, inwhich R1 is any one of the meanings indicated in Table 1 given below.

A fourth embodimental detail (detail d) of the compounds of formula Iaccording to this invention includes those compounds of formula Ic*, inwhich R1 is any one of the meanings indicated in Table 1 given below.

A fifth embodimental detail (detail e) of the compounds of formula Iaccording to this invention includes those compounds of formula Ic**, inwhich R1 is any one of the meanings indicated in Table 1 given below.

A sixth embodimental detail (detail f) of the compounds of formula Iaccording to this invention includes those compounds of formula Ib*, inwhich R1 is any one of the meanings indicated in Table 1 given below.

A seventh embodimental detail (detail g) of the compounds of formula Iaccording to this invention includes those compounds of formula Ib**, inwhich R1 is any one of the meanings indicated in Table 1 given below.

A first embodimental variant (variant a) of the compounds of formula Iaccording to this invention includes those compounds of formula I, whichare from formula Ia

A second embodimental variant (variant b) of the compounds of formula Iaccording to this invention includes those compounds of formula I, whichare from formula Ib

In the context of variant b, one subvariant of variant b includescompounds of formula Ib, in which the radicals —N(H)—C(O)— and Q arelocated at the opposite side of the plane defined by the cyclopropanering. A more precise subvariant of variant b includes compounds offormula Ib*, another more precise subvariant of variant b includescompounds of formula Ib**

If, for example, in compounds of formula Ib* Q has one of the meaningsgiven above, then the configuration—according the rules of Cahn, Ingoldand Prelog—is R in the position 2′ and R in the position 3′ as indicatedin formula Ib* above.

If, for example, in compounds of formula Ib** Q has one of the meaningsgiven above, then the configuration—according the rules of Cahn, Ingoldand Prelog—is S in the position 2′ and S in the position 3′ as indicatedin formula Ib** above.

A third embodimental variant (variant c) of the compounds of formula Iaccording to this invention includes those compounds of formula I, whichare from formula Ic

In the context of variant c, one subvariant of variant c includescompounds of formula Ic*, another subvariant of variant c includescompounds of formula Ic**

If, for example, in compounds of formula Ic* Q has the meaning phenyl orHar given above, then the configuration—according the rules of Cahn,Ingold and Prelog—is R in the position 3′ indicated in formula Ic*above.

If, for example, in compounds of formula Ic** Q has the meaning phenylor Har given above, then the configuration—according the rules of Cahn,Ingold and Prelog—is S in the position 3′ indicated in formula Ic**above.

A fourth embodimental variant (variant d) of the compounds of formula Iaccording to this invention includes those compounds of formula I, whichare from formulae Id or Id′

In one embodiment, in the meaning of this invention, among the variantsa to d, the variants a and c are to be emphasized.

In another embodiment, in the meaning of this invention, among thevariants a to d, the variant b is to be emphasized.

A fifth embodimental variant (variant e) of the compounds of formula Iaccording to this invention includes those compounds of any of theformulae Ia, Ib, Ic, Id and Id′,

in which

-   Q is optionally substituted by Rba and/or Rbb and/or Rbc, and is    phenyl, in which-   Rba has one of the meanings as defined in the compounds mentioned    above,-   Rbb has one of the meanings as defined in the compounds mentioned    above,-   Rbc has one of the meanings as defined in the compounds mentioned    above.

A subvariant (variant e1) of the compounds according to variant e ofthis invention includes those compounds of any of the formulae Ia, Ib,Ic, Id and Id′,

in which

-   Q is optionally substituted by Rba and/or Rbb, and is phenyl, in    which-   Rba is 1-4C-alkyl, halogen, trifluoromethyl, or hydroxyl,-   Rbb is 1-4C-alkyl, halogen, trifluoromethyl, or hydroxyl.

A further subvariant (variant e2) of the compounds according to variante of this invention includes those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is optionally substituted by Rba, and is phenyl, in which-   Rba is methyl, ethyl, fluorine or chlorine; especially, methyl,    fluorine or chlorine.

A further subvariant (variant e3) of the compounds according to variante of this invention includes those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is any one selected from the group consisting of phenyl,    2-chlorophenyl, 2-methylphenyl, 2-fluorophenyl, 3-chlorophenyl,    3-methylphenyl, 3-fluorophenyl, 4-chlorophenyl, 4-methylphenyl and    4-fluorophenyl; especially, 2-chlorophenyl, 2-methylphenyl,    2-fluorophenyl, 3-chlorophenyl, 3-methylphenyl and 3-fluorophenyl.

A further subvariant (variant e4) of the compounds according to variante of this invention includes those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is unsubstituted, and is phenyl.

A further subvariant (variant e5) of the compounds according to variante of this invention includes those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, ethyl, fluorine or chlorine.

A further subvariant (variant e6) of the compounds according to variante of this invention includes those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, ethyl, fluorine or chlorine.

A further subvariant (variant e7) of the compounds according to variante of this invention includes those compounds of formula Ia, Ib or Ic,

in which

-   Q is 2-(Rba)-phenyl, in which-   Rba is chlorine, methyl or ethyl.

A further subvariant (variant e8) of the compounds according to variante of this invention includes those compounds of formula Ia, Ib or Ic,

in which

-   Q is (Rbb)-substituted 2-(Rba)-phenyl, in which-   Rba is chlorine, methyl or ethyl,-   Rbb is fluorine, chlorine or methyl.

A further subvariant (variant e9) of the compounds according to variante of this invention includes those compounds of any of the formulae Ia,Ib and Ic,

in which

-   Q is 2-(Rba)-phenyl, in which-   Rba is methyl, ethyl, fluorine or chlorine; especially, methyl,    fluorine or chlorine.

A further subvariant (variant e10) of the compounds according to variante of this invention includes those compounds of any of the formulae Ia,Ib and Ic,

in which

-   Q is 3-(Rba)-phenyl, in which-   Rba is methyl, ethyl, fluorine or chlorine; especially, methyl,    fluorine or chlorine.

A further subvariant (variant e11) of the compounds according to variante of this invention includes those compounds of any of the formulae Ia,Ib and Ic,

in which

-   Q is unsubstituted, and is phenyl.

A further subvariant (variant e12) of the compounds according to variante of this invention includes those compounds of formula Ia,

in which

-   Q is unsubstituted, and is phenyl.

A further subvariant (variant e13) of the compounds according to variante of this invention includes those compounds of formula Ib,

in which

-   Q is unsubstituted, and is phenyl.

A further subvariant (variant e14) of the compounds according to variante of this invention includes those compounds of formula Ic,

in which

-   Q is unsubstituted, and is phenyl.

A sixth embodimental variant (variant f of the compounds of formula Iaccording to this invention includes those compounds of any of theformulae Ia, Ib, Ic, Id and Id′,

in which

-   Q is optionally substituted by Rca and/or Rcb, and is Har, in which-   Har is a 5-membered monocyclic heteroaryl radical comprising one to    four heteroatoms independently selected from nitrogen, oxygen and    sulphur, such as e.g. any one selected from furanyl, thiophenyl,    pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,    pyrazolyl, triazolyl, thiadiazolyl and oxadiazolyl, whereby said Har    radical is attached to the parent molecular group via a ring carbon    or ring nitrogen atom,-   Rca has one of the meanings as defined in the compounds mentioned    above,-   Rcb has one of the meanings as defined in the compounds mentioned    above.

A subvariant (variant f1) of the compounds according to variant f ofthis invention include those compounds of any of the formulae Ia, Ib,Ic, Id and Id′,

in which

-   Q is optionally substituted by Rca and/or Rcb, and is Har, in which-   Har is furanyl, thiophenyl, imidazol-1-yl or pyrazol-1-yl,-   Rca is 1-4C-alkyl,-   Rcb is 1-4C-alkyl.

A further subvariant (variant f2) of the compounds according to variantf of this invention include those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is furanyl, thiophenyl or dimethylfuranyl, such as e.g.    furan-2-yl, thiophen-2-yl or 3,4-dimethylfuran-2-yl.

A further subvariant (variant f3) of the compounds according to variantf of this invention include those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is methyl-pyrazol-1-yl, such as e.g. 5-methyl-pyrazol-1-yl.

A further subvariant (variant f4) of the compounds according to variantf of this invention include those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is furanyl, such as e.g. furan-3-yl or, especially, furan-2-yl.

A further subvariant (variant f5) of the compounds according to variantf of this invention include those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is thiophenyl, such as e.g. thiophen-3-yl or, especially,    thiophen-2-yl.

A further subvariant (variant f6) of the compounds according to variantf of this invention include those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is a radical of the following formula

which is attached to the parent molecular group via any possible ringcarbon atom, and in which

-   Rca is methyl or chlorine.

A further subvariant (variant f7) of the compounds according to variantf of this invention include those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is a radical of the following formula

which is attached to the parent molecular group via any possible ringcarbon atom, and in which

-   Rca is methyl or chlorine, and-   Rcb is attached to any possible ring carbon atom, and is methyl.

A further subvariant (variant f8) of the compounds according to variantf of this invention include those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is a radical of the following formula

which is attached to the parent molecular group via any possible ringcarbon atom, and in which

-   Rca is methyl or chlorine.

A further subvariant (variant f9) of the compounds according to variantf of this invention include those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is a radical of the following formula

which is attached to the parent molecular group via any possible ringcarbon atom, and in which

-   Rca is methyl or chlorine, and-   Rcb is attached to any possible ring carbon atom, and is methyl.

A further subvariant (variant f10) of the compounds according to variantf of this invention include those compounds of any of the formulae Ia,Ib and Ic,

in which

-   Q is 5-(Rca)-furan-2-yl, in which-   Rca is methyl or chlorine.

A further subvariant (variant f11) of the compounds according to variantf of this invention include those compounds of any of the formulae Ia,Ib and Ic,

in which

-   Q is 5-(Rca)-thiophen-2-yl, in which-   Rca is methyl or chlorine.

A further subvariant (variant f12) of the compounds according to variantf of this invention include those compounds of any of the formulae Ia,Ib and Ic,

in which

-   Q is furan-2-yl.

A further subvariant (variant f13) of the compounds according to variantf of this invention include those compounds of any of the formulae Ia,Ib and Ic,

in which

-   Q is thiophen-2-yl.

A seventh embodimental variant (variant g) of the compounds of formula Iaccording to this invention includes those compounds of any of theformulae Ia, Ib, Ic, Id and Id′,

in which

-   Q is optionally substituted by Rca and/or Rcb, and is Har, in which-   Har is a 6-membered monocyclic heteroaryl radical comprising one or    two nitrogen atoms, such as e.g. any one selected from pyridinyl,    pyrazinyl, pyridazinyl and pyrimidinyl, whereby said Har radical is    attached to the parent molecular group via a ring carbon atom,-   Rca has one of the meanings as defined in the compounds mentioned    above,-   Rcb has one of the meanings as defined in the compounds mentioned    above.

A subvariant (variant g1) of the compounds according to variant g ofthis invention include those compounds of any of the formulae Ia, Ib,Ic, Id and Id′,

in which

-   Q is optionally substituted by Rca and/or Rcb, and is Har, in which-   Har is pyridinyl,-   Rca has one of the meanings as defined in the compounds mentioned    above,-   Rcb has one of the meanings as defined in the compounds mentioned    above.

A further subvariant (variant g2) of the compounds according to variantg of this invention include those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is unsubstituted Har, in which-   Har is pyridinyl.

A further subvariant (variant g3) of the compounds according to variantg of this invention include those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is pyridin-3-yl.

A further subvariant (variant g4) of the compounds according to variantg of this invention include those compounds of any of the formulae Ia,Ib, Ic, Id and Id′,

in which

-   Q is pyridin-2-yl.

A further subvariant (variant g5) of the compounds according to variantg of this invention include those compounds of any of the formulae Ia,Ib and Ic,

in which

-   Q is unsubstituted Har, in which-   Har is pyridin-2-yl.

A further subvariant (variant g6) of the compounds according to variantg of this invention include those compounds of any of the formulae Ia,Ib and Ic,

in which

-   Q is unsubstituted Har, in which-   Har is pyridin-3-yl.

A further subvariant (variant g7) of the compounds according to variantg of this invention include those compounds of formula Ia,

in which

-   Q is unsubstituted Har, in which-   Har is pyridin-2-yl.

A further subvariant (variant g8) of the compounds according to variantg of this invention include those compounds of formula Ib,

in which

-   Q is unsubstituted Har, in which-   Har is pyridin-2-yl.

A further subvariant (variant g9) of the compounds according to variantg of this invention include those compounds of formula Ic,

in which

-   Q is unsubstituted Har, in which-   Har is pyridin-2-yl.

A further subvariant (variant g10) of the compounds according to variant9 of this invention include those compounds of formula Ia,

in which

-   Q is unsubstituted Har, in which-   Har is pyridin-3-yl.

A further subvariant (variant g11) of the compounds according to variantg of this invention include those compounds of formula Ib,

in which

-   Q is unsubstituted Har, in which-   Har is pyridin-3-yl.

A further subvariant (variant g12) of the compounds according to variantg of this invention include those compounds of formula Ic,

in which

-   Q is unsubstituted Har, in which-   Har is pyridin-3-yl.

An eighth embodimental variant (variant h) of the compounds of formula Iaccording to this invention includes those compounds of any of theformulae Ia, Ib, Ic, Id and Id′,

in which

-   Q is optionally substituted by Rda, and is Het, in which-   Het is a 3- to 7-membered monocyclic fully saturated heterocyclic    ring comprising one or two heteroatoms independently selected from    nitrogen, oxygen and sulphur,    -   such as e.g. any one selected from aziridinyl, azetidinyl,        pyrrolidinyl, piperidinyl,-   homopiperidinyl,    -   pyrazolidinyl, imidazolidinyl, piperazinyl, homopiperazinyl,        morpholinyl and thiomorpholinyl, whereby said Het radical is        attached to the parent molecular group via a ring carbon or ring        nitrogen atom,-   Rda has one of the meanings as defined in the compounds mentioned    above.

A subvariant (variant h1) of the compounds according to variant h ofthis invention include those compounds of any of the formulae Ia, Ib,Ic, Id and Id′,

in which

-   Q is unsubstituted, and is Het, in which-   Het is tetrahydrofuranyl, such as e.g. tetrahydrofuran-2-yl.

A ninth embodimental variant (variant i) of the compounds of formula Iaccording to this invention includes those compounds of any of theformulae Ia, Ib, Ic, Id and Id′,

in which

-   Q is unsubstituted, and is 3-7C-cycloalkyl, such as e.g. cyclohexyl.

A subvariant (variant i1) of the compounds according to variant i ofthis invention include those compounds of any of the formulae Ia, Ib andIc,

in which

-   Q is unsubstituted, and is cyclohexyl or cyclopentyl.

A further subvariant (variant i2) of the compounds according to variantI of this invention include those compounds of formula Ia,

in which

-   Q is unsubstituted, and is cyclohexyl.

A further subvariant (variant i3) of the compounds according to varianti of this invention include those compounds of formula Ib,

in which

-   Q is unsubstituted, and is cyclohexyl.

A further subvariant (variant i4) of the compounds according to varianti of this invention include those compounds of formula Ic,

in which

-   Q is unsubstituted, and is cyclohexyl.

A tenth embodimental variant (variant j) of the compounds of formula Iaccording to this invention includes those compounds of any of theformulae Ia, Ib, Ic, Id and Id′,

in which

-   Q is attached via a carbon atom of the benzene ring to the parent    molecular group, and is 1,3-benzodioxolyl,    2,2-difluoro-1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl,    2,3-dihydrobenzofuranyl, chromenyl or chromanyl.

An eleventh embodimental variant (variant k) of the compounds of formulaI according to this invention includes those compounds of any of theformulae Ia, Ib, Ic, Id and Id′,

in which

-   Q is any one selected from the group consisting of phenyl,    2-chlorophenyl, 2-methylphenyl, 2-fluorophenyl, 3-chlorophenyl,    3-methylphenyl, 3-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,    4-fluorophenyl,    -   furanyl, thiophenyl or dimethylfuranyl, such as e.g. furan-2-yl,        thiophen-2-yl or 3,4-dimethylfuran-2-yl,    -   methyl-pyrazol-1-yl, such as e.g. 5-methyl-pyrazol-1-yl,    -   pyridinyl, such as e.g. pyridin-3-yl,    -   tetrahydrofuranyl, such as e.g. tetrahydrofuran-2-yl, and    -   cyclohexyl.

A twelfth embodimental variant (variant l) of the compounds of formula Iaccording to this invention includes those compounds of any of theformulae Ia, Ib and Ic,

in which

-   Q is any one selected from the group consisting of 2-chlorophenyl,    2-methylphenyl, 2-fluorophenyl, 3-chlorophenyl, 3-methylphenyl,    3-fluorophenyl,    -   furanyl, thiophenyl, such as e.g. furan-2-yl or thiophen-2-yl,        and    -   pyridinyl, such as e.g. pyridin-2-yl or pyridin-3-yl.

A thirteenth embodimental variant (variant m) of the compounds offormula I according to this invention includes those compounds offormula Ia, in which Q is any one of the meanings indicated in Table 1given below.

A fourteenth embodimental variant (variant n) of the compounds offormula I according to this invention includes those compounds offormula Ic*, in which Q is any one of the meanings indicated in Table 1given below.

A fifteenth embodimental variant (variant o) of the compounds of formulaI according to this invention includes those compounds of formula Ic**,in which Q is any one of the meanings indicated in Table 1 given below.

A sixteenth embodimental variant (variant p) of the compounds of formulaI according to this invention includes those compounds of formula Ib*,in which Q is any one of the meanings indicated in Table 1 given below.

A seventeenth embodimental variant (variant q) of the compounds offormula I according to this invention includes those compounds offormula Ia, in which R1 is any one of the meanings indicated in Table 1given below.

An eighteenth embodimental variant (variant r) of the compounds offormula I according to this invention includes those compounds offormula Ic*, in which R1 is any one of the meanings indicated in Table 1given below.

A nineteenth embodimental variant (variant s) of the compounds offormula I according to this invention includes those compounds offormula Ic**, in which R1 is any one of the meanings indicated in Table1 given below.

A twentieth embodimental variant (variant t) of the compounds of formulaI according to this invention includes those compounds of formula Ib*,in which R1 is any one of the meanings indicated in Table 1 given below.

It is to be understood that the present invention includes any or allpossible combinations and subsets of the details, variants, subdetailsand subvariants defined hereinabove.

When the compounds of formula I are chiral compounds (e.g. by having oneor more chiral centers), the invention refers to all conceivablestereoisomers, like e.g. diastereomers and enantiomers, in substantiallypure form as well as in any mixing ratio, including the racemates, aswell as the salts thereof.

Accordingly, the stereoisomers of formula Ic* and of formula Ic** andthe salts thereof are part of the invention. Likewise, the stereoisomersof formula Ib* and of formula Ib** and the salts thereof are part of theinvention.

In general, enantomerically pure compounds of this invention may beprepared according to art-known processes, such as e.g. via asymmetricsyntheses, for example, by preparation and separation of appropriatediastereoisomeric compounds/intermediates, which can be separated byknown methods (e.g. by chromatographic separation or (fractional)crystallization from a suitable solvent), or by using chiral synthons orchiral reagents; by chromatographic separation on chiral separatingcolumns; by means of salt formation of the racemic compounds withoptically active acids or bases, subsequent resolution of the salts andrelease of the desired compound from the salt; by derivatization withchiral auxiliary reagents, subsequent diastereomer separation andremoval of the chiral auxiliary group; by resolution via diastereomericinclusion compounds (e.g. complexes or clathrates); by kineticresolution of a racemate (e.g. by enzymatic resolution); byenantioselective (preferential) crystallization (or crystallization byentrainment) from a conglomerate of enantiomorphous crystals undersuitable conditions; or by (fractional) crystallization from a suitablesolvent e.g. in the presence of a chiral auxiliary.

Exemplary compounds according to the present invention may include,without being restricted thereto, any compound selected from thosecompounds of formula I mentioned in the following examples, theenantiomers (e.g., when the compound is from formula Ic, in one specialembodiment, the enantiomer having the formula Ic* and, in anotherspecial embodiment, the enantiomer having the formula Ic**, or when thecompound is from formula Ib, in one special embodiment, the enantiomerhaving the formula Ib* and, in another special embodiment, theenantiomer having the formula Ib**) as well as the salts of thesecompounds and enantiomers.

As interesting exemplary compounds according to this invention any orall of the following compounds of formula Ia, in which Ra is —C(O)R1,are more worthy to be mentioned by means of the substituent meanings forR1 and Q in the Table 1 given below, as well as the salts thereof.

As other interesting exemplary compounds according to this invention anyor all of the following compounds of formula Ic, in which Ra is —C(O)R1,are more worthy to be mentioned by means of the substituent meanings forR1 and Q in the Table 1 given below, as well as the enantiomers and thesalts of these compounds and enantiomers.

As other interesting exemplary compounds according to this invention anyor all of the following compounds of formula Ic*, in which Ra is—C(O)R1, are more worthy to be mentioned by means of the substituentmeanings for R1 and Q in the Table 1 given below, as well as the saltsthereof.

As other interesting exemplary compounds according to this invention anyor all of the following compounds of formula Ic**, in which Ra is—C(O)R1, are more worthy to be mentioned by means of the substituentmeanings for R1 and Q in the Table 1 given below, as well as the saltsthereof.

As other interesting exemplary compounds according to this invention anyor all of the following compounds of formula Ib, in which Ra is —C(O)R1,are more worthy to be mentioned by means of the substituent meanings forR1 and Q in the Table 1 given below, as well as the enantiomers and thesalts of these compounds and enantiomers.

As other interesting exemplary compounds according to this invention anyor all of the following compounds of formula Ib*, in which Ra is—C(O)R1, are more worthy to be mentioned by means of the substituentmeanings for R1 and Q in the Table 1 given below, as well as the saltsthereof.

As other interesting exemplary compounds according to this invention anyor all of the following compounds of formula Ib**, in which Ra is—C(O)R1, are more worthy to be mentioned by means of the substituentmeanings for R1 and Q in the Table 1 given below, as well as the saltsthereof.

TABLE 1 R1 Q  1.) 2-(imidazol-1-yl)-ethyl pyridin-2-yl  2.)pyridin-2-yl-methyl pyridin-2-yl  3.) pyridin-3-yl-methyl pyridin-2-yl 4.) pyridin-4-yl-methyl pyridin-2-yl  5.) 2-(pyridin-2-yl)-ethylpyridin-2-yl  6.) 2-(pyridin-3-yl)-ethyl pyridin-2-yl  7.)2-(pyridin-4-yl)-ethyl pyridin-2-yl  8.) 2-(imidazol-1-yl)-ethylpyridin-3-yl  9.) pyridin-2-yl-methyl pyridin-3-yl 10.)pyridin-3-yl-methyl pyridin-3-yl 11.) pyridin-4-yl-methyl pyridin-3-yl12.) 2-(pyridin-2-yl)-ethyl pyridin-3-yl 13.) 2-(pyridin-3-yl)-ethylpyridin-3-yl 14.) 2-(pyridin-4-yl)-ethyl pyridin-3-yl 15.)2-(imidazol-1-yl)-ethyl furan-2-yl 16.) pyridin-2-yl-methyl furan-2-yl17.) pyridin-3-yl-methyl furan-2-yl 18.) pyridin-4-yl-methyl furan-2-yl19.) 2-(pyridin-2-yl)-ethyl furan-2-yl 20.) 2-(pyridin-3-yl)-ethylfuran-2-yl 21.) 2-(pyridin-4-yl)-ethyl furan-2-yl 22.)2-(imidazol-1-yl)-ethyl thiophen-2-yl 23.) pyridin-2-yl-methylthiophen-2-yl 24.) pyridin-3-yl-methyl thiophen-2-yl 25.)pyridin-4-yl-methyl thiophen-2-yl 26.) 2-(pyridin-2-yl)-ethylthiophen-2-yl 27.) 2-(pyridin-3-yl)-ethyl thiophen-2-yl 28.)2-(pyridin-4-yl)-ethyl thiophen-2-yl 29.) imidazol-1-yl-methylpyridin-2-yl 30.) hydroxymethyl pyridin-2-yl 31.) 2-hydroxyethylpyridin-2-yl 32.) imidazol-1-yl-methyl pyridin-3-yl 33.) hydroxymethylpyridin-3-yl 34.) 2-hydroxyethyl pyridin-3-yl 35.) imidazol-1-yl-methylfuran-2-yl 36.) hydroxymethyl furan-2-yl 37.) 2-hydroxyethyl furan-2-yl38.) imidazol-1-yl-methyl thiophen-2-yl 39.) hydroxymethyl thiophen-2-yl40.) 2-hydroxyethyl thiophen-2-yl 41.) 2-(imidazol-1-yl)-ethyl phenyl42.) pyridin-2-yl-methyl phenyl 43.) pyridin-3-yl-methyl phenyl 44.)pyridin-4-yl-methyl phenyl 45.) 2-(pyridin-2-yl)-ethyl phenyl 46.)2-(pyridin-3-yl)-ethyl phenyl 47.) 2-(pyridin-4-yl)-ethyl phenyl 48.)imidazol-1-yl-methyl phenyl 49.) hydroxymethyl phenyl 50.)2-hydroxyethyl phenyl 51.) 2-(imidazol-1-yl)-ethyl cyclohexyl 52.)pyridin-2-yl-methyl cyclohexyl 53.) pyridin-3-yl-methyl cyclohexyl 54.)pyridin-4-yl-methyl cyclohexyl 55.) 2-(pyridin-2-yl)-ethyl cyclohexyl56.) 2-(pyridin-3-yl)-ethyl cyclohexyl 57.) 2-(pyridin-4-yl)-ethylcyclohexyl 58.) imidazol-1-yl-methyl cyclohexyl 59.) hydroxymethylcyclohexyl 60.) 2-hydroxyethyl cyclohexyl

In the context of Table 1 above, one embodiment refers to any of thesubstituent meanings 1.) to 28.) given in the Table 1 above; anotherembodiment refers to any of the substituent meanings 29.) to 60.) givenin the Table 1 above.

Among the substituent meanings 1.) to 60.) given in the Table 1 above,the substituents meanings 1.) to 14.), 29.) to 34.), and 41.) to 60.)are to be emphasized.

Among the substituent meanings 1.) to 60.) given in the Table 1 above,the substituents meanings 2.) to 7.), 9.) to 14.), 42.) to 47.), and52.) to 57.) are to be in particular emphasized.

Compounds of formula I according to the present invention can beprepared as described below or as shown in the following reactionschemes, or as disclosed in WO2004/024066 or, particularly,WO2004/024065, the disclosure of which is incorporated herein, orsimilarly or analogously thereto according to preparation procedures orsynthesis strategies known to the person skilled in the art.

Accordingly, compounds of formula I according to the present inventioncan be obtained as specified by way of example in the followingexamples, or similarly or analogously thereto.

Thus, as shown in reaction scheme below, a compound of formula III, inwhich Ra has the meanings given above, can be condensed with malonitrilein the presence of sulfur and a suitable base, such as for example anamine (e.g. diethyl amine or morpholine) to give corresponding compoundsof formula II in a manner known to the person skilled in the art (e.g.according to a Gewald reaction) or as described in the followingexamples.

Compounds of formula III are known or can be obtained in an art-knownmanner, or analogously or similarly thereto.

Compounds of formula II can be reacted with compounds of formulaRb—C(O)—X, in which Rb has the meanings mentioned above and X is asuitable leaving group, preferably a chlorine atom, in an acylationreaction under conditions habitual per se to give the desired compoundsof formula I, in which Ra and Rb have the meanings given above.

Alternatively, compounds of the formula I can also be prepared from thecorresponding compounds of formula II and corresponding compounds offormula Rb—C(O)—X, in which X is hydroxyl, by reaction with amide bondlinking reagents known to the person skilled in the art. Exemplary amidebond linking reagents known to the person skilled in the art which maybe mentioned are, for example, the carbodiimides (e.g.dicyclohexylcarbodiimide or, preferably,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride),azodicarboxylic acid derivatives (e.g. diethyl azodicarboxylate),uronium salts [e.g. O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate]and N,N′-carbonyldiimidazole. In the scope of this invention preferredamide bond linking reagents are uronium salts and, particularly,carbodiimides, preferably, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (EDC).

Acid derivatives of formula Rb—C(O)—X are known, commercially availableor can be prepared as it is known for the skilled person, e.g. from thecorresponding carboxylic acids.

Carboxylic acids of formula Rb—C(O)—OH are known, commercially availableor can be obtained as it is habitual for the skilled person, e.g.analogously or similarly to standard procedures.

Thus, for example, carboxylic acids of formula Rb—C(O)—OH, in which Rbis -T-Q, in which T is 1-6C-alkylene, as defined above, especiallythose, in which Rb is —CH₂—CH₂-Q or —CH₂—CH(CH₃)-Q, in which Q has themeanings given above, can be obtained via CC-coupling reactions, such ase.g. by Heck or Knoevenagel reaction or, in particular, starting fromaldehydes of the formula Q-CHO or ketones, especially methylketones, ofthe formula Q-C(O)CH₃, respectively, by Horner-Wadsworth-Emmonsreaction, and then hydration reaction and, if necessary, hydrolysis ofthe corresponding esters obtained.

β-Methyl-propionic acids can be also obtained as given in J. Org. Chem.61, 16, 1996, 5510-5516 and Tetrahedron Lett. 37, 10, 1996, 1683-1686and subsequent hydration, such as e.g. described in the followingexamples, or analogously or similarly thereto.

In this context, there are several options for the synthesis ofenantomerically pure β-methyl-propionic acids known in literature, e.g.:

-   -   asymmetric addition of phenylboronic acids to α-,β-unsaturated        esters using chiral catalysts (see e.g. S. Sakuma, M. Sakai, R.        Itooka, N. Miyaura J. Org. Chem. 2000, 65, 5951-5955),    -   asymmetric Michael addition to α-,β-unsaturated esters using        chiral auxiliaries (see e.g. J. Ezquerra, L. Prieto, C.        Avendano, J. L. Martos, E. dela Cuesta, Tetrahedr. Lett. 1999,        40, 1575-1578),    -   asymmetric hydrogenation of α-,β-unsaturated esters and acids        (see e.g. T. Uemura, X. Zhang, K. Matsumura, et al., J. Org.        Chem. 1996, 61, 5510-5516; or W. Tang, W. Wang, X. Zhang Angew.        Chem. Int. Ed 2003, 42(8), 943-946), or    -   asymmetric hydrosilylation of α-,β-unsaturated esters (see        e.g. B. Lipshutz, J. M. Servesko, B. R. Taft: J. Am. Chem. Soc.        2004, 126(27), 8352-8353).

Further on, for example, carboxylic acids of formula Rb—C(O)—OH, inwhich Rb is -T-Q, in which T is 1,2-cyclopropylene and Q has themeanings given above, can be obtained, starting from aldehydes of theformula Q-CHO, via Knoevenagel or Horner-Wadsworth-Emmons reaction, andthen cyclopropanation reaction of the double bond (e.g. by Simmons-Smithreaction or, in particular, by Corey-Chaykovsky cyclopropanationreaction using dimethylsulfoxonium methylide) and, if necessary,hydrolysis of the corresponding esters obtained.

In this context, there are several options for asymmetriccyclopropanation known in literature, which may be used for thesynthesis of enantiomerically pure cyclopropanecarboxylic acids, e.g.:

-   -   asymmetric addition of a metal (e.g. Cu, Rh, Ru, Co) carbene or        carbenoid complex to an alkene (see e.g. Organic Letters 2004        Vol. 6, No. 5, 855-857),    -   catalytic asymmetric cyclopropanation using diazomethane or a        derivative thereof and a chiral transition metal (e.g. Cu)        complex (see e.g. Tetrahedron Asymmetry 2003, 14, 867-872),    -   asymmetric Simmons-Smith cyclopropanation, or    -   asymmetric Michael-initiated ring closure (MIRC) using ylides,        e.g. reaction of chiral sulfonium ylides with acrylic acid        derivatives (see e.g. Synlett 2005, 10, 1621-1623).

Aldehydes of formula Q-CHO and methylketones of formula Q-C(O)CH₃, inwhich Q has the meanings given above, are known or can be obtained in amanner customary for the skilled person analogously or similarly toknown compounds.

In an alternative synthesis route, compounds of formula VI, in which PGis a suitable temporary protective group, such as for exampletertbutoxycarbonyl (Boc) or one of those mentioned in “Protective Groupsin Organic Synthesis” by T. Greene and P. Wuts (John Wiley & Sons, Inc.1999, 3^(rd) Ed.) or in “Protecting Groups (Thieme Foundations OrganicChemistry Series N Group” by P. Kocienski (Thieme Medical Publishers,2000), can be condensed with malonitrile in the presence of sulfur and asuitable base as described above to give corresponding compounds offormula V.

Compounds of formula VI are known or can be obtained in an art-knownmanner.

Compounds of formula V can be acylated with compounds of formulaRb—C(O)—X analogously as mentioned above. Optionally, said amide bondformation can be obtained under microwave assistance. Subsequentialdeprotection of the protective group PG in a manner customary per se forthe skilled person gives compounds of formula IV, in which Rb has themeanings as mentioned above.

Compounds of formula IV can be converted into desired compounds offormula I by introduction of the group Ra via amide bond formationreaction. This amide bond formation reaction can be carried out in amanner as described afore, or analogously to the methods known to theperson skilled in the art, or as described by way of example in thefollowing examples. The appropriate starting compounds of formulaR1—C(O)—X, in which R1 and X have the meanings given above, areart-known or can be obtained according to art-known procedures oranalogously or similarly as disclosed for known compounds.

When Har-substituted carboxylic adds, in which Har has the meaningsgiven above (e.g. substituted or unsubstituted pyridyl or imidazolyl),are used as starting compounds in an amide formation reaction accordingto this invention, these carboxylic acids can be obtained viaCC-coupling reaction or nucleophilic substitution reaction ofappropriate building blocks.

Thus, e.g. Har-substituted propionic acids, in which Har has themeanings given above (e.g. substituted or unsubstituted pyridyl or1-methyl-imidazolyl) can be obtained by Heck or Knoevenagel reaction or,in particular, starting from aldehydes of the formula Har-CHO byHorner-Wadsworth-Emmons reaction, and then hydration reaction and, ifnecessary, hydrolysis of the corresponding esters obtained.

Aldehydes of the formula Har-CHO are known or can be obtained as it isknown for the skilled person, such as e.g. from the correspondingheteroaromatic compounds by formylation reaction.

Some aldehydes can be obtained as described e.g. for4-methoxy-pyridin-2-carbaldehyde in Ashimori et al, Chem Pharm Bull 38,2446-2458 (1990) or analogously or similarly thereto.

Har-substituted carboxylic acids (e.g. propionic acids), in which Harhas the meanings given above (e.g. substituted or unsubstitutedpyridyl), can be also obtained as described in WO03080607 orWO2005/030770 or analogously or similarly thereto, such as e.g.3-(4-methoxypyridin-2-yl)propionic acid is described as compound A1 inWO03080607, or analogously or similarly thereto.

It is to be understood for the skilled worker, that certain compoundsaccording to this invention can be converted into further compounds ofthis invention by art-known synthesis strategies and reactions habitualper se to a person of ordinary skill in the art.

Therefore, optionally, compounds of formula I can be also converted intofurther compounds of formula I by methods known to one of ordinary skillin the art. More specifically, for example, from compounds of theformula I in which

-   a) R2 is acyloxy, such as e.g. acetoxy, the corresponding free    hydroxyl compounds can be obtained by removal of the acyl group,    such as e.g. by saponification reaction;-   b) Het is a cyclic acetal or ketal, such as e.g. the    2,2-dimethyl-[1,3]dioxolan acetal, the corresponding free dihydroxy    compounds can be obtained by cleavage of the acetal or ketal, such    as e.g. by deacetalization reaction;-   c) R2 is an ester group, such as e.g. methoxycarbonyl, the    corresponding free carboxyl compounds can be obtained by    deesterification, such as e.g. by saponification reaction.

The methods mentioned under a) to c) can be expediently carried outanalogously to the methods known to the person skilled in the art or asdescribed by way of example in the following examples.

Optionally, compounds of the formula I can be converted into theirsalts, or, optionally, salts of the compounds of the formula I can beconverted into the free compounds. Corresponding processes are habitualper se to the skilled person.

When one of the final steps or purification is carried out under thepresence of an inorganic or organic acid (e.g. hydrochloric,trifluoroacetic, acetic or formic acid or the like), the compounds offormula I may be obtained—depending on their individual chemical natureand the individual nature of the acid used—as free base or containingsaid acid in an stoechiometric or non-stoechiometric quantity. Theamount of the acid contained can be determined according to art-knownprocedures, e.g. by titration.

It is moreover known to the person skilled in the art that if there area number of reactive centers on a starting or intermediate compound itmay be necessary to block one or more reactive centers temporarily byprotective groups in order to allow a reaction to proceed specificallyat the desired reaction center. A detailed description for the use of alarge number of proven protective groups is found, for example, in“Protective Groups in Organic Synthesis” by T. Greene and P. Wuts (JohnWiley & Sons, Inc. 1999, 3^(rd) Ed.) or in “Protecting Groups (ThiemeFoundations Organic Chemistry Series N Group” by P. Kocienski (ThiemeMedical Publishers, 2000).

The substances according to the invention are isolated and purified in amanner known per se, for example by distilling off the solvent underreduced pressure and recrystallizing the residue obtained from asuitable solvent or subjecting it to one of the customary purificationmethods, such as, for example, column chromatography on a suitablesupport material.

Salts are obtained by dissolving the free compound in a suitable solvent(e.g. a ketone, such as acetone, methyl ethyl ketone or methyl isobutylketone, an ether, such as diethyl ether, tetrahydrofuran or dioxane, achlorinated hydrocarbon, such as methylene chloride or chloroform, or alow-molecular-weight aliphatic alcohol, such as methanol, ethanol orisopropanol) which contains the desired add or base, or to which thedesired acid or base is then added. The salts are obtained by filtering,reprecipitating, precipitating with a nonsolvent for the addition saltor by evaporating the solvent. Salts obtained can be converted into thefree compounds, which can in turn be converted into salts, byalkalization or by acidification. In this manner, pharmacologicallyunacceptable salts can be converted into pharmacologically acceptablesalts.

Suitably, the conversions mentioned in this invention can be carried outanalogously or similarly to methods which are familiar per se to theperson skilled in the art.

The person skilled in the art knows on the basis of his/her knowledgeand on the basis of those synthesis routes, which are shown anddescribed within the description of this invention, how to find otherpossible synthesis routes for compounds of formula I. All these otherpossible synthesis routes are also part of this invention.

The present invention also relates to intermediates, including theirsalts, methods and processes useful in synthesizing compounds accordingto this invention.

Having described the invention in detail, the scope of the presentinvention is not limited only to those described characteristics orembodiments. As will be apparent to persons skilled in the art,modifications, analogies, variations, derivations, homologisations,alternatives and adaptations to the described invention can be made onthe base of art-known knowledge and/or, particularly, on the base of thedisclosure (e.g. the explicite, implicate or inherent disclosure) of thepresent invention without departing from the spirit and scope of thisinvention as defined by the scope of the appended claims.

The following examples serve to illustrate the invention further withoutrestricting it. Likewise, further compounds of formula I including theirsalts, whose preparation is not explicitly described, can be prepared inan analogous or similar manner or in a manner familiar per se to theperson skilled in the art using customary process techniques.

Any or all of the compounds of formula I according to the presentinvention which are mentioned in the following examples, particularlythose which are mentioned as final compounds, as well as their salts,stereoisomers and salts of the stereoisomers are a preferred subject ofthe present invention.

In the examples, MS stands for mass spectrum, M is the molecular ion inmass spectroscopy, calc. for calculated, fnd. for found, Boc for thetertbutoxycarbonyl group, EDC or EDCI for1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and otherabbreviations have their meanings customary per se to the skilledperson.

Further on, according to common practice in stereochemistry, the term“(RS)” characterizes a racemate comprising the one enantiomer having theconfiguration R and the other enantiomer having the configuration S;each of these enantiomers in pure form as well as their mixturesincluding the racemic mixtures is part of this invention.

Yet further on, according to common practice in stereochemistry, whenmore than one chiral center is present in a molecule, the symbols RS andSR are used to denote the specific configuration of each of the chiralcenters of a racemate. In more detail, for example, the term “(1RS,2RS)”stands for a racemate (racemic mixture) comprising the one enantiomerhaving the configuration (1R,2R) and the other enantiomer having theconfiguration (1S,2S); each of these enantiomers in pure form as well astheir mixtures including the racemic mixtures is part of this invention.

EXAMPLES Final Compounds

A. General Procedure for Amide Bond Formation

a) Starting from the Trifluoroacetate Salt of the Respective Free Amine:

To a solution of the appropriate acid (1.5 mmol) in dichloromethane (5ml), carbonyldiimidazole (CDI, 1.78 mmol) is added. The reaction vesselis equipped with a bubbler, the mixture is stirred until the gasevolution is completed (30 min, approximately). Then, a mixture of thesuspension of the appropriate starting trifluoroacetate salt of the freeamine in dichloromethane (10 ml) and triethylamine (0.2 g, 2 mmole) isadded to the reaction mixture. Stirring is continued for 18 to 24 hoursat room temperature, the reaction is monitored by TLC.

Work up a1: if the reaction mixture is a solution, it is extracted bythree portions of 5% sodium hydrogencarbonate (10 ml each) and once bywater (10 ml), the organic layer is evaporated and the residue subjectedto purification.

Work up a2: if the reaction mixture is a suspension, the solid productis filtered off. If the amount of this solid product is not sufficient,the mother liquour is further worked up as procedure A.

Purification: The majority of the products can be recrystallized fromacetonitrile or ethanol, in some cases by simple trituration of theorganic residue with acetonitrile or ethanol. After filtration, thecrystals are washed with diethyl ether. In case this procedure does notyield clean products, flash chromatography is performed using mixturesof dichloromethane and methanol as eluent.

b) Starting from the Respective Free Amine Using EDCI

A mixture of the appropriate starting base (1 mmol), the appropriateacid (1.5 mmol), ethyl-dimethylaminopropylcarbodiimide (EDCI, 0.29 g,1.5 mmol), 4-dimethylaminopyridine (DMAP, 0.25 g, 0.2 mmol) andwater-free dichloromethane (10 ml) are stirred at room temperature for18 to 24 hours. The reaction mixture is monitored by TLC. The reactionmixture is worked up as in the reactions carried out with CDI.

c) Using Acid Chlorides

To a suspension of the appropriate starting trifluoroacetate salt (1mmol) in dichloromethane (10 ml) triethylamine (0.4 g, 4 mmol) is added.The formed solution is added to a solution of the appropriate acidchloride (1.2 mmol) in dichloromethane (10 ml) dropwise at 0° C. withstirring and, then, stirring is continued for 24 h at room temperature.The mixture is evaporated and the residue dissolved in dichloromethane.This solution is extracted twice by water (15 ml) and once by saturatedsodium chloride solution (15 ml). Purification is carried out asdescribed in procedures a) and b).

d) Using CDI Under Microwave Assistance

3.5 eq of the appropriate acid are dissolved in dichloromethane and 2.5eq CDI is added. After the gas evolution has subsided, a solution of theappropriate amino building block in dichloromethane containing 5 eqtriethylamine is added. The reaction mixture is heated in a sealed tubefor 3 hours at 75° C. under microwave assistance. Purification iscarried out as described in procedures a) and b).

The following compounds can be prepared according to general procedure Astarting fromN-(3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide(compound A1) and the appropriate art-known carboxylic acid derivative.

-   1.    N-[3-Cyano-6-(3-pyridin-3-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3c]pyridin-2-yl]-3-phenyl-propionamide

MS: calc.: C, 25; H, 24; N, 4; O, 2; S, (444.56). fnd.: 445.2 [M+H].

-   2.    N-[3-Cyano-6-(2-pyridin-3-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-]pyridin-2-yl]-3-phenyl-propionamide

MS: calc.: C, 24; H, 22; N, 4; O, 2; S, (430.53). fnd.: 431.1 [M+H].

-   3.    N-[3-Cyano-6-(2-pyridin-2-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3c]pyridin-2-yl]-3-phenyl-propionamide

MS: calc.: C, 24; H, 22; N, 4; O, 2; S, (430.53). fnd.: 431.1 [M+H]. -4.N-[3-Cyano-6-(2-methoxy-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-]pyridin-2-yl]-3-phenyl-propionamide

MS: calc.: C, 20; H, 21; N, 3; O, 3; S, (383.47). fnd.: 384.1 [M+H].

-   5.    N-{3-Cyano-6-[2-(2-methoxy-ethoxy)-ethanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-phenyl-propionamide

MS: calc.: C, 22; H, 25; N, 3; O, 4; S, (427.53). fnd.: 428.1 [M+H].

-   6.    4-[3-Cyano-2-(3-phenyl-propanoylamino)-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-4-oxo-butyric    acid methyl ester

MS: calc.: C, 22; H, 23; N, 3; O, 4; S, (425.51). fnd.: 426 [M+H].

-   7. Acetic acid    2-[3-cyano-2-(3-phenyl-propanoylamino)-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-2-oxo-ethyl    ester

MS: calc.: C, 21; H, 21; N, 3; O, 4; S, (411.48). fnd.: 412 [M+H].

-   8.    N-[3-Cyano-6-(2-hydroxy-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-propionamide

The title compound is prepared from Example 7 by art-knownsaponification reaction (e.g. using 1N NaOH).

MS: calc.: C, 19; H, 19; N, 3; O, 3; S, (369.45).

Using similar procedures to those described herein above but withsuitable choice of starting materials (which are known or which can beobtained according to procedures customary to the skilled person ordescribed herein, or analogously or similarly thereto), the followingcompounds can be prepared.

The following compounds 49, 61, 68, 69, 71 and 83 may be obtained fromthe corresponding acetates, which can be obtained using similarprocedures to those described herein but with suitable choice ofstarting materials (e.g. similarly as to attain Example 7), by art-knownremoval of the acetyl function using for example LiOH or NaOH.

The following compounds 50, 60, 67, 70, 72 and 82 may be obtained fromthe corresponding amines and beta-propiolactone similarly to Example 48.

The following compounds 19 to 47, 51 to 59, 62 to 66, and 73 to 81 mayprepared according to general procedure A′ starting from the appropriatestarting compounds A1 to A63 and the appropriate carboxylic acids, whichare known or which can be obtained according to procedures customary tothe skilled person or described herein, or analogously or similarlythereto.

-   9. N-{3-Cyano    6-[2-(2-methoxy-ethoxy)-ethanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-furan-2-yl-propionamide

MS: calc.: C, 20; H, 23; N, 3; O, 5; S, (417.49). fnd.: 418.2.

-   10.    N-[3-Cyano-6-(2-pyridin-2-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-]pyridin-2-yl]-3-furan-2-yl-propionamide

MS: calc.: C, 22; H, 20; N, 4; O, 3; S, (420.49). fnd.: 421.2.

-   11.    N-[3-Cyano-6-(2-pyridin-3-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-]pyridin-2-yl]-3-furan-2-yl-propionamide

MS: calc.: C, 22; H, 20; N, 4; O, 3; S, (420.49). fnd.: 421.3.

-   12.    N-[3-Cyano-6-(3-pyridin-3-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide

MS: calc.: C, 23; H, 22; N, 4; O, 3; S, (434.52). fnd.: 435.2.

-   13.    N-[3-Cyano-6-(2-methoxy-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-]pyridin-2-yl]-3-furan-2-yl-propionamide

MS: calc.: C, 18; H, 19; N, 3; O, 4; S, (373.43). fnd.: 374.2.

-   14.    N-(6-Butyryl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-]pyridin-2-yl)-3-furan-2-yl-propionamide

MS: calc.: C, 19; H, 21; N, 3; O, 3; S, (371.46). fnd.: 372.

-   15.    N-[3-Cyano-6-(3-imidazol-1-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide

MS: calc.: C, 21; H, 21; N, 5; O, 3; S, (423.5). fnd.: 424.2.

-   16.    N-[3-Cyano-6-(3-imidazol-1-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-propionamide

MS: calc.: C, 23; H, 23; N, 5; O, 2; S, (433.54). fnd.: 434.2.

-   17.    N-3-Cyano-6-[3-(4-methyl-piperazin-1-yl)-propanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide

MS: calc.: C, 25; H, 31; N, 5; O, 2; S, (465.62). fnd.: 466.3.

-   18.    N-[3-Cyano-6-(3-morpholin-4-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-propionamide

MS: calc.: C, 24; H, 28; N, 4; O, 3; S, (452.58). fnd.: 453.2.

-   19.    N-[3-Cyano-6-(2-imidazol-1-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-propionamide

MS: calc.: C, 22; H, 21; N, 5; O, 2; S, (419.51). fnd.: 420.2 [M+H].

-   20.    N-[3-Cyano-6-(2-pyridin-4-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-propionamide

MS: calc.: C, 24; H, 22; N, 4; O, 2; S, (430.53). fnd.: 431.2 [M+H].

-   21.    N-{3-Cyano-6-[3-(2-methyl-benzoimidazol-1-yl)-propanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-phenyl-propionamide

MS: calc.: C, 28; H, 27; N, 5; O, 2; S, (497.62). fnd.: 498.2 [M+H].

-   22.    (RS)-N-[3-Cyano-6-(2-pyridin-2-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-butyramide

MS: calc.: C, 25; H, 24; N, 4; O, 2; S, (444.56). fnd.: 445.1 [M+H].

-   23.    (RS)-N-[3-Cyano-6-(2-pyridin-3-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-butyramide

MS: calc.: C, 25; H, 24; N, 4; O, 2; S, (444.56). fnd.: 445.3 [M+H].

-   24.    (RS)-N-[3-Cyano-6-(2-pyridin-4-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-butyramide

MS: calc.: C, 25; H, 24; N, 4; O, 2; S, (444.56). fnd.: 445.3 [M+H].

-   25.    (RS)-N-[3-Cyano-6-(3-pyridin-3-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-butyramide

MS: calc.: C, 26; H, 26; N, 4; O, 2; S, (458.59). fnd.: 459.2 [M+H].

-   26.    (RS)-N-[3-Cyano-6-(2-imidazol-1-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-]pyridin-2-yl]-3-phenyl-butyramide

MS: calc.: C, 23; H, 23; N, 5; O, 2; S, (433.54). fnd.: 434.3 [M+H].

-   27.    (RS)-N-(6-Butyryl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-butyramide

MS: calc.: C, 22; H, 25; N, 3; O, 2; S, (395.53). fnd.: 396.2 [M+H].

-   28.    N-(6-Butyryl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide

MS: calc.: C, 21; H, 23; N, 3; O, 2; S, (381.5). fnd.: 382.2 [M+H].

-   29.    (RS)-N-[3-Cyano-6-(3-pyridin-2-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-butyramide

MS: calc.: C, 26; H, 26; N, 4; O, 2; S, (458.59). fnd.: 459.1 [M+H].

-   30.    N-[3-Cyano-6-(3-pyridin-2-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-propionamide

MS: calc.: C, 25; H, 24; N, 4; O, 2; S, (444.56). fnd.: 445.1 [M+H].

-   31.    (RS)-N-[3-Cyano-6-(3-imidazol-1-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-butyramide

MS: calc.: C, 24; H, 25; N, 5; O, 2; S, (447.56). fnd.: 448.2 [M+H].

-   32.    (RS)-N-{3-Cyano-6-[3-(2-methyl-imidazol-1-yl)-propanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-phenyl-butyramide

MS: calc.: C, 25; H, 27; N, 5; O, 2; S, (461.59). fnd.: 462.2 [M+H].

-   33.    N-3-Cyano-6-[3-(2-methyl-imidazol-1-yl)-propanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide

MS: calc.: C, 24; H, 25; N, 5; O, 2; S, (447.56). fnd.: 448.2 [M+H].

-   34.    (RS)-N{3-Cyano-6-[3-(1-methyl-1H-imidazol-2-yl)-propanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-phenyl-butyramide

MS: calc.: C, 25; H, 27; N, 5; O, 2; S, (461.59). fnd.: 462.2 [M+H].

-   35.    N-{3-Cyano-6-[3-(1-methyl-1H-imidazol-2-yl)-propanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-phenyl-propionamide

MS: calc.: C, 24; H, 25; N, 5; O, 2; S, (447.56). fnd.: 448.2 [M+H].

-   36.    (RS)-N-[3-Cyano-6-(3-pyridin-4-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-butyramide

MS: calc.: C, 26; H, 26; N, 4; O, 2; S, (458.59). fnd.: 459.3 [M+H].

-   37.    (RS)-N-{3-Cyano-6-[2-(2-methyl-imidazol-1-yl)-ethanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-phenyl-butyramide

MS: calc.: C, 24; H, 25; N, 5; O, 2; S, (447.56). fnd.: 448.3 [M+H].

-   38.    N-{3-Cyano-6-[2-(2-methyl-imidazol-1-yl)-ethanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-phenyl-propionamide

MS: calc.: C, 23; H, 23; N, 5; O, 2; S, (433.54). fnd.: 434.2 [M+H].

-   39.    N-[3-Cyano-6-(3-pyridin-4-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-propionamide

MS: calc.: C, 25; H, 24; N, 4; O, 2; S, (444.56). fnd.: 445.2 [M+H].

-   40.    (RS)-N-{3-Cyano-6-[2-(4-methyl-Imidazol-1-yl)-ethanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-phenyl-butyramide

MS: calc.: C, 24; H, 25; N, 5; O, 2; S, (447.56). fnd.: 448.3 [M+H].

-   41.    N-{3-Cyano-4-[2-(4-methyl-imidazol-1-yl)-ethanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-phenyl-propionamide

MS: calc.: C, 23; H, 23; N, 5; O, 2; S, (433.54). fnd.: 434.2 [M+H].

-   42.    (RS)-N-{3-Cyano-6-[2-(2,4-dimethyl-imidazol-1-yl)-ethanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-phenyl-butyramide

MS: calc.: (C, 25; H, 27; N, 5; O, 2; S, (461,59). fnd.: 462.3 [M+H].

-   43.    N-{3-Cyano-6-[2-(2,4-dimethyl-imidazol-1-yl)-ethanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-phenyl-propionamide

MS: calc.: C, 24; H, 25; N, 5; O, 2; S, (447.56). fnd.: 448.2 [M+H].

-   44.    (RS)-N-(3-Cyano-6-[3-(4-methyl-imidazol-1-yl)-propanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-butyramide

MS: calc.: C, 25; H, 27; N, 5; O, 2; S, (461.59). fnd.: 462.3 [M+H].

-   45.    N-3-Cyano-6-[3-(4-methyl-imidazol-1-yl)-propanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamide

MS: calc.: C, 24; H, 25; N, 5; O, 2; S, (447.56). fnd.: 448.2 [M+H].

-   46.    (RS)-N-{3-Cyano-6-[3-(2,4-dimethyl-imidazol-1-yl)-propanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-phenyl-butyramide

MS: calc.: C, 26; H, 29; N, 5; O, 2; S, (475.62). fnd.: 476.3 [M+H].

47.N-{3-Cyano-6-[3-(2,4-dimethyl-imidazol-1-yl)-propanoyl]-4,5,6,7-tetrahydro-4-thieno[2,3-c]pyridin-2-yl}-3-phenyl-propionamide

MS: calc.: C, 25; H, 27; N, 5; O, 2; S, (461.59). fnd.: 462.2 [M+H].

-   48.    N-[3-Cyano-6-(3-hydroxy-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-propionamide

3 eq β-propiolactone and 1 eq of the corresponding amine (compound A1)are dissolved in pyridine and heated for 30 min under microwaveassistance at 150° C. Evaporation of the solvent and subsequentpreparative reversed phase HPLC affords the desired compound.

MS: calc.: C, 20; H, 21; N, 3; O, 3; S, (383.47). fnd.: 384.0 [M+H].

-   49.    (RS)-N-[3-Cyano-6-(2-hydroxy-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-butyramide

MS: calc.: C, 20; H, 21; N, 3; O, 3; S, (383.47). fnd.: 384.0 [M+H].

-   50.    (RS)-N-[3-Cyano-6-(3-hydroxy-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-butyramide

MS: calc.: C, 21; H, 23; N, 3; O, 3; S, (397.50). fnd.: 398.0 [M+H].

-   51.    N-[3-Cyano-6-(2-pyridin-4-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-cyclohexyl-propionamide

MS: calc.: C, 24; H, 28; N, 4; O, 2; S, (436.58).

-   52.    N-[3-Cyano-6-(2-pyridin-3-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-cyclohexyl-propionamide

MS: calc.: C, 24; H, 28; N, 4; O, 2; S, (436.58).

-   53.    N-[3-Cyano-6-(2-pyridin-2-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-cyclohexyl-propionamide

MS: calc.: C, 24; H, 28; N, 4; O, 2; S, (436.58). fnd.: 437.2 [M+H].

-   54.    N-[3-Cyano-6-(3-pyridin-4-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-cyclohexyl-propionamide

MS: calc.: C, 25; H, 30; N, 4; O, 2; S, (450.61).

-   55.    N-[3-Cyano-6-(3-pyridin-3-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-cyclohexyl-propionamide

MS: calc.: C, 25; H, 30; N, 4; O, 2; S, (450.61). fnd.: 451.3 [M+H].

-   56.    N-[3-Cyano-6-(3-pyridin-2-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-cyclohexyl-propionamide

MS: calc.: C, 25; H, 30; N, 4; O, 2; S, (450.61).

-   57.    N-[3-Cyano-6-(2-imidazol-1-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-cyclohexyl-propionamide

MS: calc.: C, 22; H, 27; N, 5; O, 2; S, (425.56).

-   58.    N-[3-Cyano-6-(3-imidazol-1-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-]pyridin-2-y]-3-cyclohexyl-propionamide

MS: calc.: C, 23; H, 29; N, 5; O, 2; S, (439.58). fnd.: 440.2 [M+H].

-   59.    N-{3-Cyano-6-[3-(1-methyl-1H-imidazol-2-yl)-propanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-cyclohexyl-propionamide

MS: calc.: C, 24; H, 31; N, 5; O, 2; S, (453.61).

-   60.    N-[3-Cyano-6-(3-hydroxy-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-cyclohexyl-propionamide

MS: calc.: C, 20; H, 27; N, 3; O, 3; S, (389.52).

-   61.    N-[3-Cyano-6-(2-hydroxy-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-cyclohexyl-propionamide

MS: calc.: C, 19; H, 25; N, 3; O, 3; S, (375.49).

-   62.    N-[3-Cyano-6-(2-pyridin-4-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide

MS: calc.: C, 22; H, 20; N, 4; O, 3; S, (420.49).

-   63.    N-[3-Cyano-6-(3-pyridin-4-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide

MS: calc.: C, 23; H, 22; N, 4; O, 3; S, (434.52).

-   64.    N-[3-Cyano-6-(3-pyridin-2-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide

MS: calc.: C, 23; H, 22; N, 4; O, 3; S, (434.52).

-   65.    N-[3-Cyano-6-(2-imidazol-1-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide

MS: calc.: C, 20; H, 19; N, 5; O, 3; S, (409.47).

-   66.    N-{3-Cyano-6-[3-(1-methyl-1H-imidazol-2-yl)-propanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-furan-2-yl-propionamide

MS: calc.: C, 22; H, 23; N, 5; O, 3; S, (437.52).

-   67.    N-[3-Cyano-6-(3-hydroxy-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide

MS: calc.: C, 18; H, 19; N, 3; O, 4; S, (373.43).

-   68.    N-[3-Cyano-6-(2-hydroxy-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide

MS: calc.: C, 17; H, 17; N, 3; O, 4; S, (359.41).

-   69.    N-[3-Cyano-6-(2-hydroxy-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-pyridin-3-yl-propionamide

MS: calc.: C, 18; H, 18; N, 4; O, 3; S, (370.43).

-   70.    N-[3-Cyano-6-(3-hydroxy-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-pyridin-3-yl-propionamide

MS: calc.: C, 19; H, 20; N, 4; O, 3; S, (384.46).

-   71.    N-[3-Cyano-6-(2-hydroxy-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-pyridin-2-yl-propionamide

MS: calc.: C, 18; H, 18; N, 4; O, 3; S, (370.43).

-   72.    N-[3-Cyano-6-(3-hydroxy-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-pyridin-2-yl-propionamide

MS: calc.: C, 19; H, 20; N, 4; O, 3; S, (384.46).

-   73. (1RS,2RS)-2-Phenyl-cyclopropanecarboxylic acid    [3-cyano-6-(2-pyridin    yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-amide

MS: calc.: C, 25; H, 22; N, 4; O, 2; S, (442.54).

-   74. (1RS,2RS)-2-Phenyl-cyclopropanecarboxylic acid    [3-cyano-6-(2-pyridin-3-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-amide

MS: calc.: C, 25; H, 22; N, 4; O, 2; S, (442.54).

-   75. (1RS,2RS)-2-Phenyl-cyclopropanecarboxylic acid    [3-cyano-6-(2-pyridinyl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-amide

MS: calc.: C, 25; H, 22; N, 4; O, 2; S, (442.54).

-   76. (1RS,2RS)-2-Phenyl-cyclopropanecarboxylic acid    [3-cyano-6-(3-pyridinyl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-amide

MS: calc.: C, 26; H, 24; N, 4; O, 2; S, (456.57).

-   77. (1RS,2RS)-2-Phenyl-cyclopropanecarboxylic acid    [3-cyano-6-(3-pyridin-3-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-amide

MS: calc.: C, 26; H, 24; N, 4; O, 2; S, (456.57).

-   78. (1RS,2RS)-2-Phenyl-cyclopropanecarboxylic acid    [3-cyano-6-(3-pyridin-2-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-amide

MS: calc.: C, 26; H, 24; N, 4; O, 2; S, (456.57).

-   79. (1RS,2RS)-2-Phenyl-cyclopropanecarboxylic acid    [3-cyano-6-(2-imidazol-1-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-amide

MS: calc.: C, 23; H, 21; N, 5; O, 2; S, (431.52).

-   80. (1RS,2RS)-2-Phenyl-cyclopropanecarboxylic acid    [3-cyano-6-(3-imidazol-1-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-amide

MS: calc.: C, 24; H, 23; N, 5; O, 2; S, (445.55).

-   81. (1RS,2RS)-2-Phenyl-cyclopropanecarboxylic acid    {3-cyano-6-[3-(1-methyl-1H-imidazol-2-yl)-propanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-amide

MS: calc.: C, 25; H, 25; N, 5; O, 2; S, (459.57).

-   82. (1RS,2RS)-2-Phenyl-cyclopropanecarboxylic acid    [3-cyano-6-(3-hydroxy-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-amide

MS: calc.: C, 21; H, 21; N, 3; O, 3; S, (395.48).

-   83. (1RS,2RS)-2-Phenyl-cyclopropanecarboxylic acid    [3-cyano-6-(2-hydroxy-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-amide

MS: calc.: C, 20; H, 19; N, 3; O, 3; S, (381.46).

The following salts are prepared according to general procedure E:

-   N-[3-cyano-6-(3-pyridin-3-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-propionamide    malonate, m.p.: 250° C.;-   N-[3-cyano-6-(3-pyridin-3-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-propionamide    L-tartrate, m.p.: 252° C.;-   N-[3-cyano-6-(3-pyridin-3-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-propionamide    maleate, m.p.: 240° C.;-   N-[3-cyano-6-(3-pyridin-3-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-propionamide    mesylate, m.p.: 165° C.;-   N-[3-cyano-6-(3-pyridin-3-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-phenyl-propionamide    oxalate, m.p.: 236° C.    Starting Materials:-   A1.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3c]pyridin-2-yl)-3-phenyl-propionamide

The title compound is prepared according to general procedure B startingfrom3-cyano-2-(3-phenyl-propanoylamino)-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylicacid tert-butyl ester (compound B1).

Using similar procedures as described to attain compound A1 or A20, butwith suitable choice of starting materials, the following compounds maybe prepared:

-   A2.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2-chlorophenyl)-propionamide-   A3.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2-methylphenyl)-propionamide-   A4.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2,3-dimethyl-phenyl)-propionamide-   A5.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2,3-dimethyl-phenyl)-propionamide-   A6.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2-chloro-3-methyl-phenyl)-propionamide-   A7.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2-chloro-5-methyl-phenyl)-propionamide-   A8.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2-fluorophenyl)-propionamide-   A9.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2-ethylphenyl)-propionamide-   A10.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(3-chlorophenyl)-propionamide-   A11.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(3-methylphenyl)-propionamide-   A12.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(3-fluorophenyl)-propionamide-   A13.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(3-ethylphenyl)-propionamide-   A14.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(pyridin-2-yl)-propionamide-   A15.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(pyridin-3-yl)-propionamide-   A16.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(pyridin-4-yl)-propionamide-   A17.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(thiophen-3-yl)-propionamide-   A18.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(thiophen-2-yl)-propionamide-   A19.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(furan-3-yl)-propionamide-   A20.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(furan-2-yl)-propionamide    200 mg of    3-cyano-2-(3-furan-2-yl-propanoylamino)-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic    acid tert-butyl ester are dissolved in 7 ml of a mixture of    dichloromethane and TFA and stirred at room temperature for 3 h.    Evaporation of the solvent gives 250 mg of the desired product as    TFA salt in sufficient purity for the next steps.

Using similar procedures as described to attain compound A1 or A20, butwith suitable choice of starting materials, the following compounds maybe prepared:

-   A21.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-butyramide-   A22.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2-chlorophenyl)-butyramide-   A23.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2-methylphenyl)-butyramide-   A24.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2,3-dimethyl-phenyl)-butyramide-   A25.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2,5-dimethyl-phenyl)-butyramide-   A26.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2-chloro-3-methyl-phenyl)-butyramide-   A27.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2-chloro-5-methyl-phenyl)-butyramide-   A28.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2-fluorophenyl)-butyramide-   A29.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2-ethylphenyl)-butyramide-   A30.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(3-chlorophenyl)-butyramide-   A31.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(3-methylphenyl)-butyramide-   A32.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(3-fluorophenyl)-butyramide-   A33.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(3-ethylphenyl)-butyramide-   A34.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(pyridin-2-yl)-butyramide-   A35.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(pyridin-3-yl)-butyramide-   A36.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(pyridin-4-yl)-butyramide-   A37.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(thiophen-3-yl)-butyramide-   A38.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(thiophen-2-yl)-butyramide-   A39.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(furan-3-yl)-butyramide-   A40.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(furan-2-yl)-butyramide-   A41.    N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-cyclohexyl)-propionamide-   A42.    (RS)-N-(3-Cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-cyclohexyl-butyramide-   A43. (1RS,2RS)-2-Phenyl-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A44. (1RS,2RS)-2-(2-Chlorophenyl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A45. (1RS,2RS)-2-(2-Methylphenyl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A46. (1RS,2RS)-2-(2,3-Dimethylphenyl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A47. (1RS,2RS)-2-(2,5-Dimethylphenyl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A48. (1RS,2RS)-2-(2-Chloro-3-methyl-phenyl)-cyclopropanecarboxylic    acid (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A49. (1RS,2RS)-2-(2-Chloro-5-methyl-phenyl)-cyclopropanecarboxylic    acid (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A50. (1RS,2RS)-2-(2-Fluorophenyl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A51. (1RS,2RS)-2-(2-Ethylphenyl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A52. (1RS,2RS)-2-(3-Chlorophenyl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A53. (1RS,2RS)-2-(3-Methylphenyl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A54. (1RS,2RS)-2-(3-Fluorophenyl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A55. (1RS,2RS)-2-(3-Ethylphenyl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-4-thieno[2,3-c]pyridin-2-yl)-amide-   A56. (1RS,2RS)-2-(Pyridin-2-yl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A57. (1RS,2RS)-2-(Pyridin-3-yl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A58. (1RS,2RS)-2-(Pyridin-4-yl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A59. (1RS,2RS)-2-(Thiophen-2-yl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A60. (1RS,2RS)-2-(Thiophen-3-yl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A61. (1RS,2RS)-2-(Furan-2-yl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide-   A62. (1RS,2RS)-2-(Furan-3-yl)-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-4-thieno[2,3-c]pyridin-2-yl)-amide-   A63. (1RS,2RS)-2-Cyclohexyl-cyclopropanecarboxylic acid    (3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-amide

B1. 3-Cyano-2-(3-phenyl-propanoylamino)4,7-dihydro-5H-thieno[2,3-c]pyridine-4-6-carboxylic acid tert-butylester

The title compound is prepared according to general procedure A d)starting from2-amino-3-cyano-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acidtert-butyl ester (compound C1) and hydrocinnamic acid. Using theappropriate carboxylic acids, further relevant starting compounds can beprepared similarly.

MS: calc.: C, 22; H, 25; N, 3; O, 3; S, (411.53). fnd.: 412.1 [M+H].

B2.3-Cyano-2-(3-pyridin-3-yl-propanoylamino)-4,7-dihydro-5H-thieno[2,3-c]pyridine-carboxylicacid tert-butyl ester

The title compound can be prepared similarly to compound B1 using theappropriate propionic acid.

MS: calc.: C, 21; H, 24; N, 4; O, 3; S, (412.51). fnd.: 413.0 [M+H].

B3.3-Cyano-2-(3-furan-2-yl-propanoylamino)-4,7-dihydro-5H-thieno[2,3-c]pyridine-carboxylicacid tert-butyl ester

7 g of 3-(2-Furyl) propionic acid are dissolved in dichloromethane and5.8 g of carbonyldiimidazole (CDI) are slowly added. After the gasevolution terminated 4 g of2-amino-3-cyano-4,7-dihydro-5H-thieno[2,3-c]pyridine-6-carboxylic acidtert-butyl ester and 10 ml of triethylamine are added and the reactionmixture is heated at 75° C. for 3,5 hours in the microwave. Flashchromatography (dichloromethane) affords the target compound in 85%yield.

C1. 2-Amino-3-cyano-4,7-dihydro-5H-thieno[2,3-c]pyridine-4-carboxylicacid tert-butyl ester

The title compound can be prepared according to general procedure Cstarting from 4-oxo-piperidine-1-carboxylic acid tert-butylester(Boc-4-piperidone) as cyclic ketone.

MS: calc.: C, 13; H, 17; N, 3; O, 2; S, (279.36). fnd.: 280.0 [M+H].

General Procedures

A′. Further General Procedure for Amide Bond Formation

1.5 eq of the appropriate carboxylic acid are dissolved in a smallamount of DMF and 1.3 eq CDI are added. After decease of the gasevolution (˜1 h) 1 eq of the appropriate amino building block and 5 eqtriethyl amine are added and the reaction mixture stirred for severalhours at room temperature.

For workup the following options are used:

In case the product precipitates from the reaction mixture it isfiltered off and triturated from ethanol. If the product does notprecipitate from the reaction mixture, the reaction mixture isconcentrated and subjected to chromatography (either preparativereversed phase HPLC or flash chromatography usingdichloromethane/methanol mixtures as eluent).

B. General Procedure for Removal of Boc Protecting Groups

The Boc protected compound is dissolved indichloromethane/trifluoroacetic acid (TFA) (2/3) and stirred for severalhours at room temperature. After evaporation of the solvent andrecrystallization from an appropriate solvent (e.g. ethanol), thedesired product is obtained as TFA salt. The TFA salt may be convertedinto the free base in a manner customary per se to the skilled person.

C. General Procedure for Condensed 2-Amino-Thiophene-3-CarbonitrileDerivatives

500 mmol of cyclic ketone and 500 mmol of malononitrile are dissolved ina minimal volume of ethanol and 500 mmol elemental sulfur are added.After addition of 500 mmol diethyl amine, the reaction mixture is heatedto 60-70° C. for some minutes and then stirred at room temperature forseveral hours. The reaction mixture is poured on ice/water and theprecipitate filtered off. In case there is no or only some precipitateformed, the aqueous layer is extracted several times withdichloromethane or another appropriate organic solvent, the combinedorganic layers are dried (e.g. MgSO₄) and concentrated in vacuo.Purification of the crude product is achieved by flash chromatographyand/or recrystallization from an appropriate solvent (e.g. ethanol).

D. General Procedure for the Preparation of Carboxylic Acids

Synthesis of propionic adds starting from aldehyde:

10 mmol of the appropriate aldehyde are dissolved with 1.1 eq. oftriethyl phosphonoacetate in 7 ml THF. At 0° C. 1 eq. of DBU is addedand the reaction mixture is stirred over night at room temperature.Then, the reaction mixture is diluted with water, acidified with aq. HCland extracted with diethyl ether. The organic layer is dried over MgSO₄and the solvent removed. This acrylic acid ester is used without furtherpurification. The crude acrylic acid ester is suspended in 20 ml 1N NaOHand stirred over night. After the reaction is completed, the reactionmixture is acidified with 1N HCl and extracted with diethyl ether. Theorganic layer is dried over MgSO₄ and the solvent evaporated; thedesired acrylic acid is obtained in almost pure form. 11 mmol of theacrylic acid are dissolved in 20 ml MeOH, 1 eq. of NAHCO₃ and 200 mgPd/C (10%) are added and the reaction hydrogenated over night at roomtemperature and normal pressure. Filtration of the reaction mixture overCelite and removal of the solvent affords the desired product in goodyield in pure form. In case one of the products is not sufficientlypure, one can also purify them via flash chromatography.

Synthesis of β-methyl propionic acid starting from acetophenone

1.9 mmol of sodium hydride are suspended in 5 ml toluene and 1.6 mmoltriethyl phosphonoacetate are added at 0° C. After stirring for 30 minat 0° C., 1.1 mmol of the appropriate acetophenone is dissolved in 1 mltoluene, added to the reaction mixture and the reaction mixture stirredover night or for several days at room temperature or heated to 60° C.After addition of some water, the reaction mixture is extracted withtoluene and the combined organic layers are dried over MgSO₄. The crudeacrylic acid ester is obtained as cis/trans mixture and used withoutfurther purification. The acrylic acid ester is suspended in a mixtureof EtOH and 1N NaOH and stirred over night at room temperature. Afteracidification with 1N HCl the acrylic acid crystallizes and can beobtained by filtration. In case no crystallization can be achieved, theacrylic acid can be purified via flash chromatography. The acrylic acidis hydrogenated in MeOH with Pd/C (10%) and 1 eq. NaHCO₃ under normalpressure at room temperature. After filtration over Celite, the solventis removed and the desired β-methyl propionic acid purified via flashchromatography if necessary.

Cyclopropanation

113 mg of sodium hydride and 1.1 g of trimethyl sulfoxonium iodide arestirred for one hour in 7 ml DMSO at room temperature. 500 mg of transcinnamic acid ethyl ester are dissolved in 6 ml DMSO/THF (1:1) and addedto the reaction mixture. After completion of the reaction (3 h, TLC) 1NHCl is added and the reaction mixture extracted with diethyl ether. Thecombined organic layers are dried over MgSO₄, the solvent removed andthe crude product (393 mg) is used without further purification. In casethe purity is not sufficient, the product can be purified by flashchromatography. Saponification of the ester to give the correspondingcarboxylic acid can be obtained similarly as described in the foregoingprocedures. Further relevant starting compounds can be obtainedsimilarly. Thus, e.g. 2-(pyridin-2-yl)-cyclopropanecarboxylic acid,2-(pyridin-3-yl)-cyclopropanecarboxylic acid and2-cyclohexyl-cyclopropanecarboxylic acid may be obtained similarly.

3-Pyridin-2-yl-butyric acid

The title compound can be obtained from the corresponding methyl ester,which is described e.g. in Lindstedt E.-L., Nilsson M., Acta Chem.Scand. Ser. B, EN, 40, 6, 1986, 466-469, by standard saponificationusing e.g. NaOH or LiOH.

3-Pyridin-3-yl-butyric acid

The title compound can be obtained from the corresponding ethyl ester,which is described e.g. in Sainsbury M., Weerasinghe D., Dolman D., J.Chem. Soc. Perkin Trans. 1, EN, 1982, 587-590, by standardsaponification using e.g. NaOH or LiOH.

Synthesis of (Di)methyl-substituted imidazol-1-yl-acetic/-propionicacids (2-Methyl-imidazol-1-yl)-acetic acid methyl ester

This compound is prepared in analogy to US2005/154024:

4 ml of bromo acetic acid methyl ester is dissolved in 30 ml DMF and 5.2g of 2-methylimidazole and 11.2 g potassium carbonate are added. Thereaction mixture is stirred at room temperature for several hours andthen subjected to aqueous work up. After removal of the solvent the pureproduct is obtained by flash chromatography in 47 to 78% yield.

(4-Methyl-imidazol-1-yl)-acetic acid methyl ester and(2,4-dimethyl-imidazol-1-yl)-acetic acid methyl ester

These compounds are prepared in analogy to(2-methyl-imidazol-1-yl)-acetic acid methyl ester and can be obtained asmixture which is used without separation of the components.

(2-Methyl-imidazol-1-yl)-propionic acid ethyl ester

2-methyl-imidazole is solved in DMF and 1 eq K₂CO₃ and 1.3 eq acrylicacid ethyl ester added. After stirring the reaction mixture over nightat room temperature, the reaction mixture is poured on water andextracted several times with dichloromethane. Removal of the solvent andflash chromatography affords the desired ethyl ester in >80% yield.

(4-Methyl-imidazol-1-yl)-propionic acid ethyl ester and(2,4-dimethyl-imidazol-1-yl)-propionic acid ethyl ester

These compounds are prepared in analogy to(2-methyl-imidazol-1-yl)-propionic acid methyl ester and can be obtainedas mixture which is used without separation of the components.

All of the aforementioned (di)methyl-substitutedimidazol-1-yl-acetic/-propionic acid esters are saponified understandard conditions to obtain the corresponding carboxylic acids.

3-Imidazol-1-yl-propionic acid can be obtained from the correspondingaldehyde similarly as described above.

3-Phenyl-butyric acid and 3-cyclohexyl-butyric acid can be obtained fromthe corresponding acetophenone similarly as described above.

Imidazol-1-yl-acetic acid, 3-imidazol-1-yl-propionic acid and3-cyclohexyl-propionic acid are known or can be obtained analogously orsimilarly to known procedures.

Relevant pyridyl-acetic acids and 3-pyridyl-propionic acids or otherrelevant acetic or propionic acid derivatives are known or can beobtained analogously or similarly to known procedures.

E. General Procedure for the Preparation of Salts of the Final Compounds

50 mg of the final compound with basic nitrogen is suspended in 1 ml ofacetone and a suspension of 1.1 eq of the corresponding acid in 1 ml ofacetone is added. Refluxing of the mixture and addition of 0.5 ml ofwater affords a clear solution from which the salt normally precipitatesupon cooling. This salt is collected and recrystallized from ethanol. Incase no or only few salt precipitates the mixture is evaporated todryness and the remaining solid is recrystallized from ethanol.

Commercial Utility

The compounds according to the present invention have miscellaneousvaluable pharmacological properties which can make them commerciallyapplicable.

The compounds according to the invention therefore can be employed astherapeutic agents for the treatment and prophylaxis of diseases inhuman and veterinary medicine.

Thus, for example, in more embodimental detail, the compounds accordingto this invention are potent and highly efficacious cell-cycle specificinhibitors of cellular (hyper)proliferation and/or inducers of apoptosisin cancer cells. Therefore, these compounds are expected to be usefulfor treating (hyper)proliferative diseases and/or disorders responsiveto the induction of apoptosis, in particular cancer.

Further on, these compounds can be useful in the treatment of benign ormalignant neoplasia. A “neoplasia” is defined by cells displayingaberrant cell proliferation and/or survival and/or a block indifferentiation. A “benign neoplasia” is described by hyperproliferationof cells, incapable of forming an aggressive, metastasizing tumorin-vivo. In contrast, a “malignant neoplasia” is described by cells withmultiple cellular and biochemical abnormalities, capable of forming asystemic disease, for example forming tumor metastasis in distantorgans.

Various diseases are caused by limitless replicative potential andaberrant cell proliferation (“hyperproliferation”) as well as evasionfrom apoptosis. These diseases include e.g. benign hypoplasia like thatof the prostate (“BPH”) or colon epithelium, psoriasias,glomerulonephritis or osteoarthritis. Most importantly these diseasesinclude malignant neoplasia commonly described as cancer andcharacterized by tumor cells finally metastasizing into distinct organsor tissues. Malignant neoplasia include solid and hematological tumors.Solid tumors are exemplified by tumors of the breast, bladder, bone,brain, central and peripheral nervus system, colon, endocrine glands (egthyroid and adrenal cortex), esophagus, endometrium, germ cells, headand neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma,sarcoma, ovary, pancreas, prostate, rectum, renal, small intestine, softtissue, testis, stomach, skin, ureter, vagina and vulva. Malignantneoplasia include inherited cancers exemplified by retinoblastoma andWilms tumor. In addition, malignant neoplasia include primary tumors insaid organs and corresponding secondary tumors in distant organs (“tumormetastases”). Hematological tumors are exemplified by aggressive andindolent forms of leukemia and lymphoma, namely non-Hodgkins disease,chronic and acute myeloid leukemia (CML/AML), acute lymphoblasticleukemia (ALL), Hodgkins disease, multiple myeloma and T-cell lymphoma.Also included are myelodysplastic syndrome, plasma cell neoplasia,paraneoplastic syndromes, cancers of unknown primary site as well asAIDS related malignancies.

It is to be noted that a cancer disease as well as a malignant neoplasiadoes not necessarily require the formation of metastases in distantorgans. Certain tumors exert devastating effects on the primary organitself through their aggressive growth properties. These can lead to thedestruction of the tissue and organ structure finally resulting infailure of the assigned organ function.

Neoplastic cell proliferation might effect normal cell behaviour andorgan function. For example the formation of new blood vessels, aprocess described as neovascularization, is induced by tumors or tumormetastases. Compounds according to this invention can be commerciallyapplicable for treatment of pathophysiological relevant processes causedby benign or neoplastic cell proliferation, such as but not limited toneovascularization by unphysiological proliferation of vascularendothelial cells.

Drug resistance is of particular importance for the frequent failure ofstandard cancer therapeutics. This drug resistance is caused by variouscellular and molecular mechanisms like overexpression of drug effluxpumps or mutation within the cellular target protein. The commercialapplicability of the compounds according to this invention is notlimited to 1^(st) line treatment of patients. Patients with resistanceto defined cancer chemotherapeutics or target specific anti-cancer drugs(2^(nd) or 3^(rd) line treatment) can be also amenable for treatmentwith the compounds according to this invention.

The compounds according to the present invention display a cell cycledependent cytotoxic activity, more precisely a mitosis confinedactivity, leading to a mitotic arrest which inevitably results in theonset of apoptosis and/or cell death.

Compounds of the present invention induce a strongly increasedphosphorylation of histone H3 when incubated with test cells for morethan 8 hours and less than 48 hours at concentrations around the IC50value of the cytotoxicity or above. Moreover, treatment of cells withcompounds of this invention does not induce polyploidy ormultinuclearity as primary mode of action.

Compounds according to the present invention can be commerciallyapplicable for treatment, prevention or amelioration of the diseases ofbenign and malignant behavior as described before, such as e.g. benignor malignant neoplasia, particularly cancer, such as e.g. any of thosecancer diseases described above.

In the context of their properties, functions and usabilities mentionedherein, the compounds according to the present invention are expected tobe distinguished by valuable and desirable effects related therewith,such as e.g. by low toxicity, superior bioavailability in general (suchas e.g. good enteral absorption), superior therapeutic window, absenceof significant side effects, and/or further beneficial effects relatedwith their therapeutic and pharmaceutical suitability (e.g. solubilitybehaviour).

The invention further includes a method for treating(hyper)proliferative diseases and/or disorders responsive to theinduction of apoptosis, particularly those diseases, disorders,conditions or illnesses mentioned above, in mammals, including humans,suffering therefrom comprising administering to said mammals in needthereof a pharmacologically active and therapeutically effective andtolerable amount of one or more of the compounds according to thisinvention.

The present invention further includes a method useful to modulateapoptosis and/or aberrant cell growth in the therapy of benign ormalignant neoplastic diseases, such as e.g. cancer, comprisingadministering to a subject in need of such therapy a therapeuticallyactive and pharmacologically effective and tolerable amount of one ormore of the compounds according to this invention.

The present invention further relates to the use of the compoundsaccording to this invention for the production of pharmaceuticalcompositions which are employed for the treatment, prophylaxis and/oramelioration of the illnesses mentioned.

The present invention further relates to the use of the compoundsaccording to this invention for the production of pharmaceuticalcompositions which can be used in the treatment, prevention oramelioration of (hyper)proliferative diseases of benign or malignantbehaviour and/or disorders responsive to the induction of apoptosis in amammal, such as, for example, benign or malignant neoplasia, e.g.cancer.

The present invention further relates to the use of the compoundsaccording to this invention for the production of pharmaceuticalcompositions which can be used use in the treatment, prevention oramelioration of disorders responsive to arresting of aberrant cellgrowth and/or induction of apoptosis.

The present invention further relates to the use of the compoundsaccording to this invention for the production of pharmaceuticalcompositions for treating, preventing or ameliorating benign ormalignant neoplasia, particularly cancer, such as e.g. any of thosecancer diseases described above.

The present invention further relates to pharmaceutical compositionscomprising one or more of the compounds according to this invention anda pharmaceutically acceptable carrier or diluent.

The present invention further relates to pharmaceutical compositionsmade by combining one or more of the compounds according to thisinvention and a pharmaceutically acceptable carrier or diluent.

The present invention further relates to pharmaceutical compositionscomprising one or more of the compounds according to this invention andpharmaceutically acceptable auxiliaries and/or excipients.

The present invention further relates to combinations comprising one ormore compounds according to this invention and pharmaceuticallyacceptable auxiliaries, excipients and/or vehicles, e.g. for treating,preventing or ameliorating benign or malignant neoplasia, particularlycancer, such as e.g. any of those cancer diseases described above.

The present invention further relates to a combination comprising acompound according to this invention and a pharmaceutically acceptableexcipient, carrier and/or diluent, e.g. for treating, preventing orameliorating benign or malignant neoplasia, particularly cancer, such ase.g. any of those cancer diseases described above.

The present invention further relates to a composition consistingessentially of a therapeutically effective and tolerable amount of oneor more compounds according to this invention together with the usualpharmaceutically acceptable vehicles, diluents and/or excipients for usein therapy, e.g. for treating, preventing or amelioratinghyperproliferative diseases, such as e.g. cancer, and/or disordersresponsive to induction of apoptosis.

The present invention further relates to compounds according to thisinvention for use in therapy, such as, for example, in the treatment,prevention or amelioration (hyper)proliferative diseases of benign ormalignant behaviour and/or disorders responsive to the induction ofapoptosis, such as e.g. those diseases mentioned herein, particularlycancer.

The present invention further relates to compounds according to thisinvention having anti-proliferative and/or apoptosis inducing activity.

The present invention further relates to pharmaceutical compositionsaccording to this invention having anti-proliferative activity.

The present invention further relates to pharmaceutical compositionsaccording to this invention having apoptosis inducing activity.

The invention further relates to the use of a pharmaceutical compositioncomprising one or more of the compounds according to this invention assole active ingredient(s) and a pharmaceutically acceptable carrier ordiluent in the manufacture of pharmaceutical products for the treatmentand/or prophylaxis of the illnesses mentioned above.

Additionally, the invention relates to an article of manufacture, whichcomprises packaging material and a pharmaceutical agent contained withinsaid packaging material, wherein the pharmaceutical agent istherapeutically effective inhibiting cellular (hyper)proliferationand/or inducing apoptosis, ameliorating the symptoms of a(hyper)proliferative disease and/or a disorder responsive to theinduction of apoptosis, and wherein the packaging material comprises alabel or package insert which indicates that the pharmaceutical agent isuseful for treating, preventing or ameliorating a (hyper)proliferativedisease and/or a disorder responsive to the induction of apoptosis, andwherein said pharmaceutical agent comprises one or more compoundsaccording to the invention. The packaging material, label and packageinsert otherwise parallel or resemble what is generally regarded asstandard packaging material, labels and package inserts forpharmaceuticals having related utilities.

The pharmaceutical compositions according to this invention are preparedby processes which are known per se and familiar to the person skilledin the art. As pharmaceutical compositions, the compounds of theinvention (=active compounds) are either employed as such, or preferablyin combination with suitable pharmaceutical auxiliaries and/orexcipients, e.g. in the form of tablets, coated tablets, dragees, pills,cachets, granules, capsules, caplets, suppositories, patches (e.g. asTTS), emulsions (such as e.g. micro-emulsions or lipid emulsions),suspensions (such as e.g. nano suspensions), gels, solubilisates orsolutions (e.g. sterile solutions), or encapsuled in liposomes or asbeta-cyclodextrine inclusion complexes or the like, the active compoundcontent advantageously being between 0.1 and 95% and where, by theappropriate choice of the auxiliaries and/or excipients, apharmaceutical administration form (e.g. a delayed release form or anenteric form) exactly suited to the active compound and/or to thedesired onset of action can be achieved.

The person skilled in the art is familiar with auxiliaries, vehicles,excipients, diluents, carriers or adjuvants which are suitable for thedesired pharmaceutical formulations, preparations or compositions onaccount of his/her expert knowledge. In addition to solvents, gelformers, ointment bases and other active compound excipients, forexample antioxidants, dispersants, emulsifiers, pre-servatives,solubilizers (such as e.g. polyoxyethylenglyceroltriricinoleat 35, PEG400, Tween 80 or the like), colorants, complexing agents, permeationpromoters, stabilizers, fillers, binders, thickeners, disintegratingagents, buffers, pH regulators (e.g. to obtain neutral, alkaline oracidic formulations), polymers, lubricants, coating agents, propellants,tonicity adjusting agents, surfactants, flavorings, sweeteners or dyes,can be used.

In particular, auxiliaries and/or excipients of a type appropriate tothe desired formulation and the desired mode of administration are used.

The administration of the compounds, pharmaceutical compositions orcombinations according to the invention may be performed in any of thegenerally accepted modes of administration available in the art.Illustrative examples of suitable modes of administration includeintravenous, oral, nasal, parenteral, topical, transdermal and rectaldelivery. Oral and intravenous delivery are preferred.

For the treatment of dermatoses, the compounds of the invention can bein particular administered in the form of those pharmaceuticalcompositions which are suitable for topical application. For theproduction of the pharmaceutical compositions, the compounds of theinvention (=active compounds) are preferably mixed with suitablepharmaceutical auxiliaries and further processed to give suitablepharmaceutical formulations. Suitable pharmaceutical formulations are,for example, powders, emulsions, suspensions, sprays, oils, ointments,fatty ointments, creams, lotions, pastes, gels or solutions.

The pharmaceutical compositions according to the invention are preparedby processes known per se. The dosage of the compounds of the invention(=active compounds) is carried out in the order of magnitude customaryfor inhibitors of cellular (hyper)proliferation or apoptosis inducers.Topical application forms (such as ointments) for the treatment ofdermatoses thus contain the active compounds in a concentration of, forexample, 0.1-99%. The customary dose in the case of systemic therapy(p.o.) may be between 0.03 and 60 mg/kg per day, (i. v.) may be between0.03 and 60 mg/kg/h. In another embodiment, the customary dose in thecase of systemic therapy (p.o.) is between 0.3 and 30 mg/kg per day, (i.v.) is between 0.3 and 30 mg/kg/h.

The choice of the optimal dosage regime and duration of medication,particularly the optimal dose and manner of administration of the activecompounds necessary in each case can be determined by a person skilledin the art on the basis of his/her expert knowledge.

Depending upon the particular disease, to be treated or prevented,additional therapeutic active agents, which are normally administered totreat or prevent that disease, may optionally be coadministered with thecompounds according to this invention. As used herein, additionaltherapeutic agents that are normally administered to treat or prevent aparticular disease are known as appropriate for the disease beingtreated.

For example, compounds according to this invention may be combined withone or more standard therapeutic agents used for treatment of thediseases as mentioned before.

In one particular embodiment, compounds according to this invention maybe combined with one or more art-known ant-cancer agents, such as e.g.with one or more chemotherapeutic and/or target specific anti-canceragents as described below.

Examples of known chemotherapeutic anti-cancer agents frequently used incombination therapy include, but not are limited to (i)alkylating/carbamylating agents such as Cyclophosphamid (Endoxan®),Ifosfamid (Holoxan®), Thiotepa (Thiotepa Lederle®), Melphalan(Alkeran®), or chloroethylnitrosourea (BCNU); (ii) platinum derivativeslike cis-platin (Platinex® BMS), oxaliplatin or carboplatin (Cabroplat®BMS); (iii) antimitotic agents/tubulin inhibitors such as vincaalkaloids (vincristine, vinblastine, vinorelbine), taxanes such asPaclitaxel (Taxol®), Docetaxel (Taxotere®) and analogs as well as newformulations and conjugates thereof, epothilones such as Epothilone B(Patupilone®), Azaepothilone (Ixabepilone®) or ZK-EPO, a fully syntheticepothilone B analog; (iv) topoisomerase inhibitors such asanthracyclines (exemplified by Doxorubicin/Adriblastin®),epipodophyllotoxines (exemplified by Etoposide/Etopophos®) andcamptothecin and camptothecin analogs (exemplified byIrinotecan/Camptosar® or Topotecan/Hycamtin®); (v) pyrimidineantagonists such as 5-fluorouracil (5-FU), Capecitabine (Xeloda®),Arabinosylcytosine/Cytarabin (Alexan®) or Gemcitabine (Gemzar®); (vi)purin antagonists such as 6-mercaptopurine (Puri-Nethol®), 6-thioguanineor fludarabine (Fludara®) and finally (vii) folic acid antagonists suchas methotrexate (Farmitrexat®) or premetrexed (Alimta®).

Examples of target specific anti-cancer drug classes used inexperimental or standard cancer therapy include but are not limited to(i) kinase inhibitors such as e.g. Imatinib (Glivec®), ZD-1839/Gefitinib(Iressa®), Bay43-9006 (Sorafenib), SU11248/Sunitinib (Sutent®) orOSI-774/Erlotinib (Tarceva®); (ii) proteasome inhibitors such asPS-341/Bortezumib (Velcade®); (iii) histone deacetylase inhibitors likeSAHA, PXD101, MS275, MGCD0103, Depsipeptide/FK228, NVP-LBH589,NVP-LAQ824, Valproic acid (VPA) and butyrates (iv) heat shock protein 90inhibitors like 17-allylaminogeldanamycin (17-AAG); (v) vasculartargeting agents (VTAs) like combretastin A4 phosphate or AVE8062/AC7700and anti-angiogenic drugs like the VEGF antibodies, such as Bevacizumab(Avastin®), or KDR tyrosine kinase inhibitors such as PTK787/ZK222584(Vatalanib); (vi) monoclonal antibodies such as Trastuzumab (Herceptin®)or Rituximab (MabThera/Rituxan®) or Alemtuzumab (Campath®) or Tositumab(Bexxar®) or C225/Cetuximab (Erbitux®) or Avastin (see above) as well asmutants and conjugates of monoclonal antibodies, e.g. Gemtuzumabozogamicin (Mylotarg®) or Ibritumomab tiuxetan (Zevalin®), and antibodyfragments; (vii) oligonucleotide based therapeutics likeG-3139/Oblimersen (Genasense®); (viii) Toll-like receptor/TLR 9 agonistslike Promune®, TLR 7 agonists like Imiquimod (Aldara®) or Isatoribineand analogues thereof, or TLR 7/8 agonists like Resiquimod as well asimmunostimulatory RNA as TLR 7/8 agonists; (ix) protease inhibitors (x)hormonal therapeutics such as anti-estrogens (e.g. Tamoxifen orRaloxifen), anti-androgens (e.g. Flutamide or Casodex), LHRH analogs(e.g. Leuprolide, Goserelin or Triptorelin) and aromatase inhibitors.

Other known target specific anti-cancer agents which may be used forcombination therapy include bleomycin, retinoids such as all-transretinoic acid (ATRA), DNA methyltransferase inhibitors such as the2-deoxycytidine derivative Decitabine (Docagen®) and 5-Azacytidine,alanosine, cytokines such as interleukin-2, interferons such asinterferon α2 or interferon-γ, death receptor agonists, such as TRAIL,DR4/5 agonistic antibodies, FasL and TNF-R agonists.

As exemplary anti-cancer agents, which may be useful in the combinationtherapy according to the present invention, any of the following drugsmay be mentioned, without being restricted thereto, 5 FU, actinomycin D,ABARELIX, ABCIXIMAB, ACLARUBICIN, ADAPALENE, ALEMTUZUMAB, ALTRETAMINE,AMINOGLUTETHIMIDE, AMIPRILOSE, AMRUBICIN, ANASTROZOLE, ANCITABINE,ARTEMISININ, AZATHIOPRINE, BASILIXIMAB, BENDAMUSTINE, BEVACIZUMAB,BEXXAR, BICALUTAMIDE, BLEOMYCIN, BORTEZOMIB, BROXURIDINE, BUSULFAN,CAMPATH, CAPECITABINE, CARBOPLATIN, CARBOQUONE, CARMUSTINE, CETRORELIX,CHLORAM-BUCIL, CHLORMETHINE, CISPLATIN, CLADRIBINE, CLOMIFENE,CYCLOPHOSPHAMIDE, DACARBAZINE, DACLIZUMAB, DACTINOMYCIN, DAUNORUBICIN,DECITABINE, DESLORELIN, DEXRAZOXANE, DOCETAXEL, DOXIFLURIDINE,DOXORUBICIN, DROLOXIFENE, DROSTANOLONE, EDELFOSINE, EFLORNITHINE,EMITEFUR, EPIRUBICIN, EPITIOSTANOL, EPTAPLATIN, ERBITUX, ERLOTINIB,ESTRAMUSTINE, ETOPOSIDE, EXEMESTANE, FADROZOLE, FINASTERIDE,FLOXURIDINE, FLUCYTOSINE, FLUDARABINE, FLUOROURACIL, FLUTAMIDE,FORMESTANE, FOSCARNET, FOSFESTROL, FOTEMUSTINE, FULVESTRANT, GEFITINIB,GENASENSE, GEMCITABINE, GLIVEC, GOSERELIN, GUSPERIMUS, HERCEPTIN,IDARUBICIN, IDOXURIDINE, IFOSFAMIDE, IMATINIB, IMPROSULFAN, INFLIXIMAB,IRINOTECAN, IXABEPILONE, LANREOTIDE, LETROZOLE, LEUPRORELIN, LOBAPLATIN,LOMUSTINE, LUPROLIDE, MELPHALAN, MERCAPTOPURINE, METHOTREXATE,METUREDEPA, MIBOPLATIN, MIFEPRISTONE, MILTEFOSINE, MIRIMOSTIM,MITOGUAZONE, MITOLACTOL, MITOMYCIN, MITOXANTRONE, MIZORIBINE, MOTEXAFIN,MYLOTARG, NARTOGRASTIM, NEBAZUMAB, NEDAPLATIN, NILUTAMIDE, NIMUSTINE,OCTREOTIDE, ORMELOXIFENE, OXALI-PLATIN, PACLITAXEL, PALIVIZUMAB,PATUPILONE, PEGASPARGASE, PEGFILGRASTIM, PEMETREXED, PENTETREOTIDE,PENTOSTATIN, PERFOSFAMIDE, PIPOSULFAN, PIRARUBICIN, PLICAMYCIN,PREDNIMUSTINE, PROCARBAZINE, PROPAGERMANIUM, PROSPIDIUM CHLORIDE,RALOXIFEN, RALTITREXED, RANIMUSTINE, RANPIRNASE, RASBURICASE, RAZOXANE,RITUXIMAB, RIFAMPICIN, RITROSULFAN, ROMURTIDE, RUBOXISTAURIN,SARGRAMOSTIM, SATRAPLATIN, SIROLIMUS, SOBUZOXANE, SORAFENIB,SPIROMUSTINE, STREPTOZOCIN, SUNITINIB, TAMOXIFEN, TASONERMIN, TEGAFUR,TEMOPORFIN, TEMOZOLOMIDE, TENIPOSIDE, TESTOLACTONE, THIOTEPA,THYMALFASIN, TIAMIPRINE, TOPOTECAN, TOREMIFENE, TRAIL, TRASTUZUMAB,TREOSULFAN, TRIAZIQUONE, TRIMETREXATE, TRIPTORELIN, TROFOSFAMIDE,UREDEPA, VALRUBICIN, VATALANIB, VERTEPORFIN, VINBLASTINE, VINCRISTINE,VINDESINE, VINORELBINE, VOROZOLE and ZEVALIN.

The anti-cancer agents mentioned herein above as combination partners ofthe compounds according to this invention are meant to includepharmaceutically acceptable derivatives thereof, such as e.g. theirpharmaceutically acceptable salts.

The person skilled in the art is aware on the base of his/her expertknowledge of the kind, total daily dosage(s) and administration form(s)of the additional therapeutic agent(s) coadministered. Said total dailydosage(s) can vary within a wide range.

In practicing the present invention, the compounds according to thisinvention may be administered in combination therapy separately,sequentially, simultaneously, concurrently or chronologically staggered(such as e.g. as combined unit dosage forms, as separate unit dosageforms, as adjacent discrete unit dosage forms, as fixed or non-fixedcombinations, as kit-of-parts or as admixtures) with one or morestandard therapeutics, in particular art-known anti-cancer agents(chemotherapeutic and/or target specific anti-cancer agents), such ase.g. any of those mentioned above.

In this context, the present invention further relates to a combinationcomprising

-   a first active ingredient, which is at least one compound according    to this invention, and-   a second active ingredient, which is at least one art-known    anti-cancer agent, such as e.g. one or more of those mentioned    herein above,-   for separate, sequential, simultaneous, concurrent or    chronologically staggered use in therapy, such as e.g. in therapy of    any of those diseases mentioned herein.

The term “combination” according to this invention may be present as afixed combination, a non-fixed combination or a kit-of-parts.

A “fixed combination” is defined as a combination wherein the said firstactive ingredient and the said second active ingredient are presenttogether in one unit dosage or in a single entity. One example of a“fixed combination” is a pharmaceutical composition wherein the saidfirst active ingredient and the said second active ingredient arepresent in admixture for simultaneous administration, such as in aformulation. Another example of a “fixed combination” is apharmaceutical combination wherein the said first active ingredient andthe said second active ingredient are present in one unit without beingin admixture.

A “kit-of-parts” is defined as a combination wherein the said firstactive ingredient and the said second active ingredient are present inmore than one unit. One example of a “kit-of-parts” is a combinationwherein the said first active ingredient and the said second activeingredient are present separately. The components of the kit-of-partsmay be administered separately, sequentially, simultaneously,concurrently or chronologically staggered.

The present invention further relates to a pharmaceutical compositioncomprising a first active ingredient, which is at least one compoundaccording to this invention, and a second active ingredient, which is atleast one art-known ant-cancer agent, such as e.g. one or more of thosementioned herein above, and, optionally, a pharmaceutically acceptablecarrier or diluent, for separate, sequential, simultaneous, concurrentor chronologically staggered use in therapy.

The present invention further relates to a combination productcomprising

-   a.) at least one compound according to this invention formulated    with a pharmaceutically acceptable carrier or diluent, and-   b.) at least one art-known anti-cancer agent, such as e.g. one or    more of those mentioned herein above, formulated with a    pharmaceutically acceptable carrier or diluent.

The present invention further relates to a kit-of-parts comprising apreparation of a first active ingredient, which is a compound accordingto this invention, and a pharmaceutically acceptable carrier or diluent;a preparation of a second active ingredient, which is an art-knownanti-cancer agent, such as one of those mentioned above, and apharmaceutically acceptable carrier or diluent; for simultaneous,concurrent, sequential, separate or chronologically staggered use intherapy. Optionally, said kit comprises instructions for its use intherapy, e.g. to treat (hyper)proliferative diseases and/or disordersresponsive to the induction of apoptosis, such as e.g. cancer, moreprecisely, any of those cancer diseases described above.

The present invention further relates to a combined preparationcomprising at least one compound according to this invention and atleast one art-known anti-cancer agent for simultaneous, concurrent,sequential or separate administration.

In this connection, the present invention further relates tocombinations, compositions, formulations, preparations or kits accordingto the present invention having anti-proliferative and/or apoptosisinducing properties.

In addition, the present invention further relates to a method fortreating in combination therapy (hyper)proliferative diseases and/ordisorders responsive to the induction of apoptosis, such as e.g. cancer,in a patient comprising administering a combination, composition,formulation, preparation or kit as described herein to said patient inneed thereof.

In addition, the present invention further relates to a method fortreating (hyper)proliferative diseases of benign or malignant behaviourand/or disorders responsive to the induction of apoptosis, such as e.g.cancer, in a patient comprising administering in combination therapyseparately, simultaneously, concurrently, sequentially orchronologically staggered a pharmaceutically active and therapeuticallyeffective and tolerable amount of a pharmaceutical composition, whichcomprises a compound according to this invention and a pharmaceuticallyacceptable carrier or diluent, and a pharmaceutically active andtherapeutically effective and tolerable amount of one or more art-knownanti-cancer agents, such as e.g. one or more of those mentioned herein,to said patient in need thereof.

In further addition, the present invention relates to a method fortreating, preventing or ameliorating (hyper)proliferative diseasesand/or disorders responsive to induction of apoptosis, such as e.g.benign or malignant neoplasia, e.g. cancer, particularly any of thosecancer diseases mentioned herein, in a patient comprising administeringseparately, simultaneously, concurrently, sequentially orchronologically staggered to said patient in need thereof an amount of afirst active compound, which is a compound according to the presentinvention, and an amount of at least one second active compound, said atleast one second active compound being a standard therapeutic agent,particularly at least one art-known anticancer agent, such as e.g. oneor more of those chemotherapeutic and target-specific anti-cancer agentsmentioned herein, wherein the amounts of the first active compound andsaid second active compound result in a therapeutic effect.

In yet further addition, the present invention relates to a method fortreating, preventing or ameliorating (hyper)proliferative diseasesand/or disorders responsive to induction of apoptosis, such as e.g.benign or malignant neoplasia, e.g. cancer, particularly any of thosecancer diseases mentioned herein, in a patient comprising administeringa combination according to the present invention.

In addition, the present invention further relates to the use of acomposition, combination, formulation, preparation or kit according tothis invention in the manufacture of a pharmaceutical product, such ase.g. a commercial package or a medicament, for treating, preventing, orameliorating (hyper)proliferative diseases, such as e.g. cancer, and/ordisorders responsive to the induction of apoptosis, particularly thosediseases mentioned herein, such as e.g. malignant or benign neoplasia.

The present invention further relates to a commercial package comprisingone or more compounds of the present invention together withinstructions for simultaneous, concurrent, sequential or separate usewith one or more chemotherapeutic and/or target specific anti-canceragents, such as e.g. any of those mentioned herein.

The present invention further relates to a commercial package consistingessentially of one or more compounds of the present invention as soleactive ingredient together with instructions for simultaneous,concurrent, sequential or separate use with one or more chemotherapeuticand/or target specific anti-cancer agents, such as e.g. any of thosementioned herein.

The present invention further relates to a commercial package comprisingone or more chemotherapeutic and/or target specific anti-cancer agents,such as e.g. any of those mentioned herein, together with instructionsfor simultaneous, concurrent, sequential or separate use with one ormore compounds according to the present invention.

The compositions, combinations, preparations, formulations, kits orpackages mentioned in the context of the combination therapy accordingto this invention may also include more than one of the compoundsaccording to this invention and/or more than one of the art-knownanti-cancer agents mentioned.

The first and second active ingredient of a combination or kit-of-partsaccording to this invention may be provided as separate formulations(i.e. independently of one another), which are subsequently broughttogether for simultaneous, concurrent, sequential, separate orchronologically staggered use in combination therapy; or packaged andpresented together as separate components of a combination pack forsimultaneous, concurrent, sequential, separate or chronologicallystaggered use in combination therapy.

The type of pharmaceutical formulation of the first and second activeingredient of a combination or kit-of-parts according to this inventioncan be similar, i.e. both ingredients are formulated in separate tabletsor capsules, or can be different, i.e. suited for differentadministration forms, such as e.g. one active ingredient is formulatedas tablet or capsule and the other is formulated for e.g. intravenousadministration.

The amounts of the first and second active ingredients of thecombinations, compositions or kits according to this invention maytogether comprise a therapeutically effective amount for the treatment,prophylaxis or amelioration of a (hyper)proliferative diseases and/or adisorder responsive to the induction of apoptosis, particularly one ofthose diseases mentioned herein, e.g. benign or malignant neoplasia,especially cancer, like any of those cancer diseases mentioned herein.

In addition, compounds according to the present invention can be used inthe pre- or post-surgical treatment of cancer.

In further addition, compounds of the present invention can be used incombination with radiation therapy.

A combination according to this invention can refer to a compositioncomprising both the compound(s) according to this invention and theother active anti-cancer agent(s) in a fixed combination (fixed unitdosage form), or a medicament pack comprising the two or more activeingredients as discrete separate dosage forms (non-fixed combination).In case of a medicament pack comprising the two or more activeingredients, the active ingredients are preferably packed into blistercards which are suited for improving compliance.

Each blister card preferably contains the medicaments to be taken on oneday of treatment. If the medicaments are to be taken at different timesof day, the medicaments can be disposed in different sections on theblister card according to the different ranges of times of day at whichthe medicaments are to be taken (for example morning and evening ormorning, midday and evening). The blister cavities for the medicamentsto be taken together at a particular time of day are accommodated in therespective range of times of day. The various times of day are, ofcourse, also put on the blister in a clearly visible way. It is alsopossible, of course, for example to indicate a period in which themedicaments are to be taken, for example stating the times.

The daily sections may represent one line of the blister card, and thetimes of day are then identified in chronological sequence in thiscolumn.

Medicaments which must be taken together at a particular time of day areplaced together at the appropriate time on the blister card, preferablya narrow distance apart, allowing them to be pushed out of the blistereasily, and having the effect that removal of the dosage form from theblister is not forgotten.

Biological Investigations

The anti-proliferative/cytotoxic activity of the compounds describedherein, can be tested on subclones of RKO (RKOp27) human colonadenocarcinoma cells (Schmidt et al., Oncogene 19, 2423-2429; 2000)using the Alamar Blue cell viability assay (described in O'Brien et al.Eur J Biochem 267, 5421-5426, 2000). The compounds are dissolved as 20mM solutions in dimethylsulfoxide (DMSO) and subsequently diluted insemi-logarithmic steps. DMSO dilutions are further diluted 1:100 intoDulbecco's modified Eagle's medium (DMEM) containing 10% fetal calfserum to a final concentration twice as much as the final concentrationin the test. RKO subclones are seeded into 96 well flat bottom plates ata density of 5000 cells per well in a volume of 50 μl per well. 24 hoursafter seeding the 50 μl each of the compound dilutions in DMEM mediumare added into each well of the 96 Well plate. Each compound dilution istested as quadruplicates. Wells containing untreated control cells arefilled with 50 μl DMEM medium containing 1% DMSO. The cells are thenincubated with the substances for 72 hours at 37° C. in a humidifiedatmosphere containing 5% carbon dioxide. To determine the viability ofthe cells, 10 μl of an Alamar Blue solution (Biosource) are added andthe fluorescence is measured at an extinction of 544 nm and an emissionof 590 nm. For the calculation of the cell viability the emission valuefrom untreated cells is set as 100% viability and the emission rates oftreated cells are set in relation to the values of untreated cells.Viabilities are expressed as % values.

The corresponding IC₅₀ values of the compounds foranti-proliferative/cytotoxic activity are determined from theconcentration-effect curves.

Representative IC₅₀ values for anti-proliferation/cytotoxicitydetermined in the mentioned assay follow from the following table A, inwhich the numbers of the compounds correspond to the numbers of theexamples.

TABLE A Anti-proliferative/cytotoxic activity IC₅₀ RKO p27 induced IC₅₀RKO p27 induced IC₅₀ RKO p27 induced (arrested) >100 μM (arrested) ≧40μM (arrested) ≧10 μM IC₅₀ RKO p27 2, 3, 4, 7, 9, 10, 11, 12, 37 34, 35uninduced 13, 14, 15, 16, 20, 22, (proliferating) ≦0.3 μM 23, 24, 28,30, 38, 39, 41, 53 IC₅₀ RKO p27 1, 5, 18, 19, 21, 25, 26, 17, 40, 43 32,33, 36, 42, 45 uninduced 27, 29, 31, 58 (proliferating) ≧0.3 μM but ≦2μM

To determine the cell cycle specific mode of action, subclones of RKOcolon adenocarcinoma cells (RKOp27 or RKOp21 as described by Schmidt etal. in Oncogene 19, 2423-2429; 2000) are seeded into 96 well flat bottomplates at a density of 15000 cells per well in a volume of 50 μl perwell in DMEM growth medium with 10% FCS containing 10 μM Ponasterone A.24 hours after seeding the 50 μl each of the compound dilutions in DMEMmedium are added into each well of the 96 Well plate. Each compounddilution is tested as quadruplicates. Wells containing untreated controlcells are filled with 50 μl DMEM medium containing 1% DMSO. The cellsare then incubated with the substances for 72 hours at 37° C. in ahumidified atmosphere containing 5% carbon dioxide. To determine theviability of the cells, 10 μl of an Alamar Blue solution (Biosource) areadded and the fluorescence was measured at an extinction of 544 nm andan emission of 590 nm. For the calculation of the cell viability theemission value from untreated cells is set as 100% viability and theemission rates of treated cells are set in relation to the values ofuntreated cells. Viabilities are expressed as % values. Viability iscompared of proliferating cells grown in the absence of the inducerPonasterone A, versus viability of cells arrested by the expression ofectopic p27Kip1 induced by Ponasterone A.

To test the anti-proliferative activity/cytotoxicity on cells known tobe highly resistant towards distinct classes of chemotherapeutics, HCT15cells (with P-glycoprotein overexpression) and MCF7 ADR cells, both ofthem are known to overexpress certain classes of multidrug resistancetransporters are used in Alamar Blue assays as described above. Briefly,the compounds are dissolved as 20 mM solutions in dimethylsulfoxide(DMSO) and subsequently diluted in semi-logarithmic steps. DMSOdilutions were further diluted 1:100 into Dulbecco's modified Eagle'smedium (DMEM) containing 10% fetal calf serum to a final concentrationtwice as much as the final concentration in the test. The cells to betested are seeded into 96 well flat bottom plates at a density of 10000cells per well in a volume of 50 μl per well. 24 hours after seeding the50 μl each of the compound dilutions in DMEM medium are added into eachwell of the 96 Well plate. Each compound dilution is tested asquadruplicates. Wells containing untreated control cells are filled with50 μl DMEM medium containing 1% DMSO.

The cells are then incubated with the substances for 72 hours at 37° C.in a humidified atmosphere containing 5% carbon dioxide. To determinethe viability of the cells, 10 μl of an Alamar Blue solution (Biosource)are added and the fluorescence was measured at an extinction of 544 nmand an emission of 590 nm. For the calculation of the cell viability theemission value from untreated cells is set as 100% viability and theemission rates of treated cells are set in relation to the values ofuntreated cells. Viabilities are expressed as % values.

The induction of apoptosis can be measured by using a Cell deathdetection ELISA (Roche Biochemicals, Mannheim, Germany). RKO subclonesare seeded into 96 well flat bottom plates at a density of 10000 cellsper well in a volume of 50 μl per well. 24 hours after seeding the 50 μleach of the compound dilutions in DMEM medium are added into each wellof the 96 Well plate. Each compound dilution is tested at least astriplicates. Wells containing untreated control cells are filled with 50μl DMEM medium containing 1% DMSO. The cells are then incubated with thesubstances for 24 hours at 37° C. in a humidified atmosphere containing5% carbon dioxide. As a positive control for the induction of apoptosis,cells are treated with 50 μM Cisplatin (Gry Pharmaceuticals,Kirchzarten, Germany). Medium is then removed and the cells are lysed in200 μl lysis buffer. After centrifugation as described by themanufacturer, 10 μl of cell lysate is processed as described in theprotocol. The degree of apoptosis is calculated as follows: Theabsorbance at 405 nm obtained with lysates from cells treated with 50 μMcisplatin is set as 100 cpu (cisplatin units), while an absorbance at405 nm of 0.0 was set as 0.0 cpu. The degree of apoptosis is expressedas cpu in relation to the value of 100 cpu reached with the lysatesobtained from cells treated with 50 μM cisplatin.

1. A compound of formula I

wherein Ra is —C(O)R1, R1 is 1-4C-alkyl, or 1-4C-alkyl substituted byone to four substituents independently selected from R2, Rb is -T-Q, inwhich T is 1-6C-alkylene or 3-7C-cycloalkylene, Q is optionallysubstituted by Rca and/or Rcb, and is Har, each R2 is the same ordifferent and is independently selected from the group consisting of:3-7C-cycloalkyl, phenyl, Har, Het, halogen, trifluoromethyl, nitro,cyano, —C(O)R3, —C(O)OR4, —C(O)N(R5)R6, —S(O)₂R3, —S(O)₂N(R5)R6,—N(R7)C(O)R3, —N(R7)C(O)OR4, —N(R7)C(O)N(R5)R6, guanidino, —OC(O)R3,completely or predominantly fluorine-substituted 1-4C-alkoxy,—O[C(R8)R9]_(y)N(R5)R6, —O[C(R8)R9]_(y)C(O)N(R5)R6, —OR4,hydroxy-2-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, pyridyl-1-4C-alkoxy,(1-4C-alkoxy-2-4C-alkoxy)-2-4C-alkoxy, —N(R5)R6, and —SR3, wherein eachof said 3-7C-cycloalkyl, phenyl, Har and Het is optionally substitutedby one to four substituents independently selected from R10, each R3,R4, R5 and R6 is the same or different and is each independentlyselected from the group consisting of: hydrogen, 1-7C-alkyl,3-7C-cycloalkyl, phenyl, and phenyl-1-4C-alkyl, each R7 is the same ordifferent and is independently selected from the group consisting of:hydrogen, 1-7C-alkyl, and 3-7C-cycloalkyl, each R8 and R9 is the same ordifferent and is each independently selected from the group consistingof: hydrogen, and 1-4C-alkyl, each R10 is the same or different isindependently selected from the group consisting of: 1-4C-alkyl, phenyl,halogen, trifluoromethyl, cyano, 1-4C-alkoxycarbonyl, carboxyl,hydroxyl, and phenoxy, wherein each of said phenyl and phenoxy radicalscan be unsubstituted or optionally substituted by up to four halogenradicals and up to two 1-4C-alkyl, hydroxyl, trifluoromethyl or cyanoradicals, each y is 1, 2, 3 or 4, each Rca, and Rcb is the same ordifferent and is each independently selected from the group consistingof: 1-4C-alkyl, phenyl, halogen, trifluoromethyl, cyano,1-4C-alkoxycarbonyl, carboxyl, hydroxyl, and phenoxy, wherein each ofsaid phenyl and phenoxy can be unsubstituted or optionally substitutedby up to four halogen radicals and up to two 1-4C-alkyl, hydroxyl,trifluoromethyl or cyano radicals, each Har is the same or different andis independently a fully aromatic or partially aromatic mono- or fusedbicyclic ring or ring system, which contains at least one heteroatom inthe ring or ring system, made up of a first constituent being a 5- or6-member monocyclic unsaturated, aromatic heteroaryl ring A, whichheteroaryl ring A comprises one to four heteroatoms independentlyselected from the group consisting of nitrogen, oxygen and sulfur, and,optionally, fused to said first constituent, a second constituent beinga benzene ring, a 5-6C-cycloalkane ring, an additional heteroaryl ring Aas defined herein afore, or a heterocyclic ring B, whereby said Har isattached via a substitutable ring carbon or ring nitrogen atom of Har,each Het is the same or different and is independently a fully saturatedor partially unsaturated mono- or fused bicyclic ring or ring systemmade up of a first constituent being a 3- to 7-membered monocyclic fullysaturated or partially unsaturated, non-aromatic heterocyclic ring B,which heterocyclic ring B comprises one to three heteroatomsindependently selected from the group consisting of nitrogen, oxygen andsulfur, and which heterocyclic ring B is optionally substituted by oneor two oxo groups, and, optionally, fused to said first constituent, asecond constituent being a benzene ring, a 3-7C-cycloalkane ring, or anadditional heterocyclic ring B as defined herein afore, wherein said Hetis attached via a substitutable ring carbon or ring nitrogen atom; underthe proviso, that(6-acetyl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-propionamideis disclaimed; or a salt thereof.
 2. A compound according to claim 1,which is a compound of one of the formulae Ia, Ib, Ic, Id and Id′

wherein Ra is —C(O)R1, R1 is 1-4C-alkyl, or 1-C-alkyl substituted by oneor two substituents independently selected from R2, Q is optionallysubstituted by Rca and/or Rcb, and is Har, each R2 is the same ordifferent and is independently selected from the group consisting of:Har, Het, —C(O)R3, —C(O)OR4, —C(O)N(R5)R6, —N(R7)C(O)R3, —OC(O)R3, —OR4,hydroxy-2-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy, pyridyl-1-4C-alkoxy,(1-4C-alkoxy-2-4C-alkoxy) -2-4C-alkoxy, and phenyl-1-4C-alkoxy, whereineach of said Har and Het is optionally substituted by one or twosubstituents independently selected from R10, each R3, R4, R5 and R6 isthe same or different and is each independently selected from the groupconsisting of: hydrogen, and 1-4C-alkyl, each R7 is the same ordifferent and is independently selected from the group consisting of:hydrogen, and 1-4C-alkyl, each R10 is the same or different isindependently selected from the group consisting of: 1-4C-alkyl,halogen, trifluoromethyl, cyano, 1-4C-alkoxycarbonyl, carboxyl, andhydroxyl, each Rca and Rcb is the same or different and is eachindependently selected from the group consisting of: 1-4C-alkyl,halogen, trifluoromethyl, cyano, 1-4C-alkoxycarbonyl, carboxyl, andhydroxyl, each Har is the same or different and is independently a5-membered monocyclic heteroaryl radical comprising one heteroatomindependently selected from the group consisting of nitrogen, oxygen andsulphur, wherein said Har is attached via a ring carbon or ring nitrogenatom of Har, or a 6-membered monocyclic heteroaryl radical comprisingone or two nitrogen atoms, whereby said Har is attached via a ringcarbon atom of Har, Het is a 3- to 7-membered monocyclic fully saturatedheterocyclic ring comprising one or two heteroatoms independentlyselected from the group consisting of nitrogen, oxygen and sulphur,whereby said Het is attached via a ring carbon or ring nitrogen atom; orsalt thereof.
 3. A compound according to claim 1, which is a compound ofone of the formulae Ia, Ib, Ic, Id and Id′

wherein Ra is —C(O)R1, R1 is 1-4C-alkyl, 1-4C-alkyl substituted by onesubstituent selected from R2, or 3-4C-alkyl substituted by two hydroxylradicals on different carbon atoms, Q is optionally substituted by Rcaand/or Rcb, and is pyridinyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl,thiazolyl, oxazolyl or imidazolyl, each R2 is the same or different andis independently selected from the group consisting of: Har, morpholino,4-methyl-piperazin-1-yl, —C(O)R3, —C(O)OR4, —C(O)N(R5)R6, —N(R7)C(O)R3,—OC(O)R3, —OR4, hydroxy-2-4C-alkoxy, 1-4C-alkoxy-2-4C-alkoxy,pyridyl-1-4C-alkoxy, phenyl-1-4C-akoxy, and(1-4C-alkoxy-2-4C-alkoxy)-2-4C-alkoxy, wherein said Har is optionallysubstituted by one or two substituents independently selected from R10,each R3, R4, R5 and R6 is the same or different and is eachindependently selected from the group consisting of: hydrogen, and1-4C-alkyl, R7 is hydrogen, Har is bonded via a ring carbon atom or aring nitrogen atom of Har, and is imidazolyl, pyrazolyl or triazolyl, orHar is bonded via a ring carbon atom of Har, and is pyridinyl, pyrazinylor pyrimidinyl, R10 is 1-4C-alkyl, each Rca and Rcb is the same ordifferent and is each independently selected from the group consistingof: 1-4C-alkyl, fluorine, chlorine, trifluoromethyl, and cyano; or asalt thereof.
 4. A compound according to claim 1, which is a compound ofone of the formulae Ia, Ib and Ic

wherein Ra is —C(O)R1, R1 is 1-4C-alkyl, or 1-4C-alkyl which issubstituted by one substituent selected from R2, or 1-2C-alkyl which issubstituted by 2,2-dimethyl-[1,3]dioxolan-4-yl, or 3-4C-alkyl which issubstituted by two hydroxyl radicals on different carbon atoms, Q isoptionally substituted by Rca and/or Rcb, and is pyridinyl, furanyl,thiophenyl or pyrazo1-yl, each R2 is the same or different and isindependently selected from the group consisting of: pyridyl,pyrimidinyl, R201- and/or R202-substituted pyridyl, R201- and/orR202-substituted pyrimidinyl, morpholino, imidazol-1-yl, pyrazol-1-yl,mono- or di-(R201)-substituted imidazol-1-yl, mono- ordi-(R201)-substituted pyrazol-1-yl, 1N-(1-4C-alkyl)-imidazolyl,1N-(1-4C-alkyl)-pyrazol -1-yl, R201-substituted1N-(1-4C-alkyl)-imidazolyl, R201-substituted1N-(1-4C-alkyl)-pyrazol-1-yl, 1N-(H)-imidazolyl, 1N-(H)-pyrazol-1-yl,R201-substituted 1N-(H)-imidazolyl, R201-substituted1N-(H)-pyrazol-1-yl, —C(O)OR4, —OC(O)R3, —OR4, phenyl-1-2C-alkoxy,1-2C-alkoxy-2-3C-alkoxy, and (1-2C-alkoxy-2-3C-alkoxy)-2-3C-alkoxy, R3is 1-4C-alkyl, each R4 is the same or different and is independentlyselected from the group consisting of: hydrogen, and 1-4C-alkyl, R201 is1-4C-alkyl, R202 is 1-4C-alkyl, each Rca and Rcb is the same ordifferent and is each independently selected from the group consistingof: methyl, ethyl, fluorine, chlorine, and trifluoromethyl; or a saltthereof.
 5. A compound according to claim 1, which is a compound of oneof the formulae Ia, Ib and Ic

wherein Ra is —C(O)R1, in which R1 is methyl, ethyl or propyl, or R1 is(R2)-methyl, 2-(R2)-ethyl, or 3-(R2)-propyl, or R1 is2,3-dihydroxypropyl, Q is unsubstituted, and is pyridinyl, furanyl orthiophenyl, or Q is substituted by Rca and/or Rcb, and is pyridinyl,furanyl or thiophenyl, each R2 is the same or different and isindependently selected from the group consisting of: pyridyl,pyrimidinyl, methybsubstituted pyridyl, imidazol-1-yl, mono- ordi-methyl-substituted imidazol-1-yl, 1N-methyl-imidazolyl, carboxylmethoxycarbonyl, hydroxyl, methylcarbonyloxy, methoxy, ethoxy,benzyloxy, and 2-methoxyethoxy, each Rca and Rcb is the same ordifferent and is each independently selected from the group consistingof: methyl, ethyl and chlorine; or a salt thereof.
 6. A compoundaccording to claim 1, which is a compound of one of the formulae Ia, Iband Ic

wherein Ra is —C(O)R1, R1 is (R2)-methyl, or 2-(R2)-ethyl, in which R2is pyridyl, or R1is (R2)-methyl, in which R2 is 1N-methyl-imidazolyl, orR1 is (R2)-methyl, or 2-(R2)-ethyl, in which R2 is hydroxyl or methoxy,or R1 is (2-methoxyethoxy)-methyl, or R1 is (R2)-methyl, or2-(R2)-ethyl, in which R2 is imidazol-1-yl, or mono- ordi-methyl-substituted imidazol-1-yl; Q is unsubstituted, and ispyridinyl, or Q is unsubstituted, and is furanyl, or Q is unsubstituted,and is thiophenyl, or Q is 5-(Rca)-furan-2-yl, in which Rca is methyl orchlorine, or Q 5-(Rca)-4-(Rcb)-furan-2-yl, in which Rca is methyl orchlorine, Rcb is methyl, or Q is 5-(Rca)-thiophen-2-yl, in which Rca ismethyl or chlorine, or a salt thereof.
 7. A compound according to claim1, which is a compound of one of the formulae Ia, Ib and Ic

wherein Ra is —C(O)R1, R1 is (R2)-methyl, or 2-(R2)-ethyl, in which R2is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, or R1 is (R2)-methyl, inwhich R2 is 1-methyl-imidazol-2-yl or 1-methyl-imidazol-5-yl, or R1 is(R2)-methyl, or 2-(R2)-ethyl, in which R2 is hydroxyl, or R1 is(R2)-methyl, or 2(R2)-ethyl, in which R2 is imidazol-1-yl,2-methyl-imidazol-1-yl, 4-methyl-imidazol-1-yl or2,4-dimethyl-imidazol-1-yl; Q is unsubstituted, and is pyridin-2-yl, orQ is unsubstituted, and is pyridin-3-yl, or Q is unsubstituted, and isfuran-2-yl, or Q is unsubstituted, and is thiophen-2-yl, or a saltthereof.
 8. A compound according to claim 1, which is a compound of oneof the formulae Ia, Ib and Ic

wherein Ra is —C(O)R1, in which R1 is (R2)-methyl, or 2-(R2)-ethyl, inwhich R2 is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, or R1 is(R2)-methyl, or 2-(R2)-ethyl, in which R2 is hydroxyl, or R1 is(R2)-methyl, or 2-(R2)-ethyl, in which R2 is imidazol-1-yl; Q isunsubstituted, and is pyridin-2-yl, or Q is unsubstituted, and ispyridin-3-yl, or Q is unsubstituted, and is furan-2-yl, or a saltthereof.
 9. A compound according to claim 1, which is a compound of oneof the formulae Ia and Ic

wherein Ra is —C(O)R1, R1 is (R2)-methyl, or 2-(R2)-ethyl, in which R2is pyridyl, or R1 is (R2)-methyl, or 2-(R2)-ethyl, in which R2 ismethoxy, or R1 is (2-methoxyethoxy)-methyl, or R1 is (R2)-methyl, or2-(R2)-ethyl, in which R2 is imidazol-1-yl; Q is unsubstituted, and ispyridinyl, or Q is unsubstituted, and is furanyl, or Q is unsubstituted,and is thiophenyl, or Q is 5-(Rca)-furan-2-yl, in which Rca is methyl orchlorine, or Q 5-(Rca)-4-(Rcb)-furan-2-yl, in which Rca is methyl orchlorine, Rcb is methyl, or Q is 5-(Rca)-thiophen-2-yl, in which Rca ismethyl or chlorine; or a salt thereof.
 10. A compound according to claim1, which is a compound of one of the formulae Ia and Ic

wherein Ra is —C(O)R1, R1 is (R2)-methyl, or 2-(R2)-ethyl, in which R2is pyridyl, or R1 is 2-(R2)-ethyl, in which R2 is imidazol-1-yl; Q isunsubstituted, and is pyridin-2-yl, or Q is unsubstituted, and ispyridin-3-yl, or Q is unsubstituted, and is furan-2-yl, or Q isunsubstituted, and is thiophen-2-yl, or a salt thereof.
 11. A compound,which is selected from the group consisting ofN-{3-Cyano-6-[2-(2-methoxy-ethoxy)-ethanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-furan-2-yl-propionamide,N-[3-Cyano-6-(2-pyridin-2-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide,N-(3-Cyano-6-(2-pyridin-3-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide,N-[3-Cyano-6-(3-pyridin-3-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-furan-2-yl-propionamide,N-[3-Cyano-6-(2-methoxy-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide,N-(6-Butyryl-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-furan-2-yl-propionamide,N-[3-Cyano-6-(3-imidazol-1-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide,N-[3-Cyano-6-(2-pyridin-4-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide,N-[3-Cyano-6-(3-pyridin-4-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide,N-[3-Cyano-6-(3-pyridin-2-yl-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide,N-[3-Cyano-6-(2-imidazol-1-yl-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide,N-{3-Cyano-6[3-(1-methyl-1H-imidazol-2-yl)-propanoyl]-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl}-3-furan-2-yl-propionamide,N-[3-Cyano-6-(3-hydroxy-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide,N3-Cyano-6-(2-hydroxy-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-furan-2-yl-propionamide,N-[3-Cyano-6-(2-hydroxy-ethanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-pyridin-3-yl-propionamide,N-[3-Cyano-6-(3-hydroxy-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-pyridin-3-yl-propionamide,N-[3-Cyano-6-(2-hydroxy-ethanoyl)-4,5,6,7-tetrahyduo-thieno[2,3-c]pyridin-2-yl]-3-pyridin-2-yl-propionamideandN-[3-Cyano-6-(3-hydroxy-propanoyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl]-3-pyridin-2-yl-propionamide,and salts thereof.
 12. An enantiomer of a compound according to claim 1,or a salt thereof.
 13. A pharmaceutical composition comprising one ormore compounds according to claim 1, together with a pharmaceuticallyacceptable excipient, diluent and/or carrier.
 14. A combinationcomprising a first active ingredient, which is at least one compoundaccording to claim 1, and a second active ingredient, which is at leastone anti-cancer agent selected from the group consisting ofchemotherapeutic anti-cancer agents and target-specific anti-canceragents.
 15. The combination according to claim 14, in which saidchemotherapeutic anti-cancer agents are selected from the groupconsisting of (i) alkylating/carbamylating agents; (ii) platinumderivatives; (iii) antimitotic agents/tubulin inhibitors; (iv)topoisomerase inhibitors; (v) pyrimidine antagonists; (vi) purinantagonists; and (vii) folic acid antagonists.
 16. The combinationaccording to claim 14, in which said target-specific anti-cancer agentsare selected from the group consisting of (i) kinase inhibitors; (ii)proteasome inhibitors; (iii) histone deacetylase inhibitors; (iv) heatshock protein 90 inhibitors; (v) vascular targeting agents,anti-angiogenic drugs, and KDR tyrosine kinase inhibitors; (vi)monoclonal antibodies, mutants and conjugates of monoclonal antibodies,and antibody fragments; (vii) oligonucleotide based therapeutics; (viii)Toll-like receptor/TLR 9 agonists, TLR 7 agonists and TLR 7/8 agonists;(ix) protease inhibitors; (x) hormonal therapeutics; (xi) aromataseinhibitors; (xii) bleomycin; (xiii) retinoids; (xiv) DNAmethyltransferase inhibitors; (xv) alanosine; (xvi) cytokines; (xvii)interferons; (xviii) death receptor agonists; (xix) DR4/5 agonisticantibodies; (xx) FasL; and (xxi) TNF-R agonists.